A two-stage technique uses induced biologic membranes with delayed placement of bone graft. Excellent clinical results have been reported with reconstruction of segmental bone defects >20 cm. A bioactive membrane is created via place-ment of a temporary polymethyl methacrylate spacer. The membrane appears to mature biochemically and physically 4 to 8 weeks after spacer placement.
A two-stage technique uses induced biologic membranes with delayed placement of bone graft. Excellent clinical results have been reported with reconstruction of segmental bone defects >20 cm. A bioactive membrane is created via place-ment of a temporary polymethyl methacrylate spacer. The membrane appears to mature biochemically and physically 4 to 8 weeks after spacer placement.
A two-stage technique uses induced biologic membranes with delayed placement of bone graft. Excellent clinical results have been reported with reconstruction of segmental bone defects >20 cm. A bioactive membrane is created via place-ment of a temporary polymethyl methacrylate spacer. The membrane appears to mature biochemically and physically 4 to 8 weeks after spacer placement.
Loss Abstract Multiple surgeries are often required to manage segmental bone loss because of the complex mechanics and biology involved in reconstruction. These procedures can lead to prolonged recovery times, poor patient outcomes, and even delayed amputation. A two- stage technique uses induced biologic membranes with delayed placement of bone graft to manage this clinical challenge. In the rst stage, a polymethyl methacrylate spacer is placed in the defect to produce a bioactive membrane, which appears to mature biochemically and physically 4 to 8 weeks after spacer placement. In the second, cancellous autograft is placed within this membrane and, via elution of several growth factors, the membrane appears to prevent graft resorption and promote revascularization and consolidation of new bone. Excellent clinical results have been reported, with successful reconstruction of segmental bone defects >20 cm. R econstruction of large segmental bone defects is often challeng- ing. The goal is to achieve a func- tional, stable extremity in an expe- dient manner that will be well tolerated. However, most techniques for reconstruction of significant bone loss are associated with lengthy heal- ing or rehabilitation times and un- predictable union rates, or they use methods that are poorly tolerated. Current management options include intercalary bone transport and dis- traction osteogenesis, vascularized bone transfer, massive cancellous autograft transfer, and synthetic calcium-based fillers. These options may be supplemented with the addi- tion of demineralized bone matrix, allograft, or bone morphogenetic protein (BMP). Recently, use of induced mem- branes has shown potential as an al- ternative reconstruction method for large segmental bone defects. A bio- active membrane is created via place- ment of a temporary polymethyl methacrylate (PMMA) spacer, and the membrane is later filled with can- cellous autograft. History and Development Traditionally, patients with signifi- cant soft-tissue injury associated with bone loss underwent amputa- tion; however, limb salvage has be- come increasingly common, with re- ported clinical outcomes comparable to those of amputation at short-term follow-up. 1 As limb salvage efforts increase, surgeons continue to strive for successful management of large segmental bone defects. Autogenous bone graft remains the optimal graft for management of these defects be- Benjamin C. Taylor, MD Bruce G. French, MD T. Ty Fowler, MD Jeremy Russell, DO Attila Poka, MD From the Department of Orthopedics, Grant Medical Center (Dr. Taylor, Dr. French, Dr. Russell, and Dr. Poka) and the Department of Orthopedic Surgery, Mount Carmel Medical Center (Dr. Fowler), Columbus, OH. Dr. Taylor or an immediate family member has received research or institutional support from Synthes. Dr. French or an immediate family member serves as a paid consultant to Biomet. Dr. Russell or an immediate family member has stock or stock options held in Orthovita. Dr. Poka or an immediate family member is a member of a speakers bureau or has made paid presentations on behalf of Stryker and serves as a paid consultant to Biomet. Neither Dr. Fowler nor any immediate family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article. J Am Acad Orthop Surg 2012;20: 142-150 http://dx.doi.org/10.5435/ JAAOS-20-03-142 Copyright 2012 by the American Academy of Orthopaedic Surgeons. Review Article 142 Journal of the American Academy of Orthopaedic Surgeons cause of its osteoinductive, osteocon- ductive, and osteogenic properties. However, this graft has several draw- backs and limitations, including a fi- nite supply and risk of significant morbidity or iatrogenic injury with harvest. 2 In addition, outcomes asso- ciated with massive cancellous au- tograft of large segmental defects are often poor due to substantial graft resorption, even in noninfected, well- vascularized surgical sites. 3,4 The concept of creating a mem- brane to protect and enhance the lo- cal environment was proposed in the early 1960s; the initial materials tested were nonabsorbable sub- stances such as Teflon and polyure- thane sponges. 5-7 Preventing graft re- sorption while enhancing the local biologic environment has been achieved with porous resorbable polymeric membranes, which not only limit graft resorption but also allow for increased bone healing through neovascularization and ex- clusion of nonosseous tissues. 7,8 Fur- ther research on the use of these membranes has been reported in the periodontal and craniomaxillofacial literature, along with techniques that describe regeneration of periodontal bone, a process called guided tissue regeneration. 6 Masquelet and colleagues 9,10 devel- oped the use of induced membrane- assisted massive autograft for seg- mental bony defects and successfully managed defects 25 cm with associ- ated severe soft-tissue injury by use of this technique. Reported advan- tages of this technique include pro- tection against autograft resorption, relative maintenance of graft posi- tion, and prevention of soft-tissue in- terposition. 11 This technique was dis- covered largely by accident; the induction of this membrane was an unanticipated finding. Masquelet and Begue 12 used cement spacers to manage infected nonunions with bone loss, and the resultant mem- brane was initially maintained at the time of final grafting only to limit surgical devitalization and subse- quent blood loss. Basic Science Principles The induced membrane is a unique and potent tissue thought to be re- sponsible for early clinical success in managing large bone defects. The role of the membrane in healing has been examined in animal models, re- sulting in improved understanding of the structure and biologic properties of this membrane. Histologic and immunochemical analysis has re- vealed that the membrane is made of a type I collagen-heavy matrix, and fibroblastic cells are the dominant cell type. 11,13 The inner aspect of the membrane is epithelial-like and com- posed of fibroblasts, myofibroblasts, and collagen bundles that run paral- lel to the surface of the membrane. 12 This tissue is highly vascularized, and the PMMA spacer causes a mild foreign-body inflammatory response; giant cells and macrophages were discovered on histologic evaluation. 11 The limited inflammatory response has been shown to decrease after the second week following spacer im- plantation and to disappear by 6 months following bone grafting. 14,15 The reaction produced by the PMMA spacer is milder than that in- duced by other membrane materials; use of silicone spacers is often associ- ated with intense T-cell and giant cell reactions and formation of a vascu- larized pseudosynovium. 11,16 The membrane contains a high concentration of vascular endothelial growth factor, an angiogenic factor that has been shown to increase the vascularity of the surrounding tis- sue. 13 In addition, increased levels of core-binding factor -1, a critical transcription factor for osteoblastic cell development, have been found in the fibroblastic cells within the mem- brane. 17 Further analysis of mem- brane protein has revealed that in- creased levels of transforming growth factor-1 and BMP-2 are present after implantation of the PMMA spacer; BMP-2 production peaks at 4 weeks postimplantation, which suggests that an optimal time for definitive bone grafting exists. 13 Biochemical analysis has shown that membrane protein extract stimulates bone marrow cell proliferation as well as mesenchymal cell differentia- tion to osteoblastic cell lineage. 13 Investigation of the biochemical characteristics of the membrane con- tinues; these characteristics have im- plications for the development of the induced membrane technique and tissue engineering. In various animal models, a fibrous membrane was successfully formed when a PMMA spacer was placed in the area of the segmental bony defect in a purely subcutaneous posi- tion. 14,15 At 6 weeks postoperatively, the spacer was removed, and the in- duced membranes were noted to be 1 to 2 mm thick, well vascularized, and nonadherent to the underlying spacer. These membranes served to eliminate soft-tissue interposition into the defect and created a semi- rigid cavity to accept bone graft. The shape and size of the healed bone graft is defined by the membrane. In addition, the membrane was shown to prevent ectopic bone formation by maintaining the position of the graft. 10 In models in which the spacer was removed and was not replaced with bone graft, limited bone forma- tion on the internal aspect of the membrane, but not within it, has been reported. 12,13 This suggests that the membrane may have inherent os- teogenic properties; however, this possibility has not been proved. The membrane has been shown to main- tain the volume of bone graft placed in the defect, which may be the result Benjamin C. Taylor, MD, et al March 2012, Vol 20, No 3 143 of greater bone formation, decreased bone resorption, and/or prevention of soft-tissue ingrowth associated with the use of induced mem- branes. 11,12,14,15 Local depot delivery of antibiot- ics via an antibiotic-impregnated PMMA spacer can achieve antibiotic concentration levels many times greater than the bacterial minimum inhibitory concentration, with negli- gible increases in serum or plasma levels and little systemic toxicity. 18 The selection of antibiotics that can be used with a spacer is more limited than that available for use via other routes because antibiotics used with a spacer must be thermostable to withstand the often significant exo- thermic reaction associated with PMMA curing. In addition, the anti- biotic must be hydrophilic to diffuse into the surrounding tissues. 19 Com- monly used antibiotics include genta- micin, tobramycin, vancomycin, and various cephalosporins. 18-24 Dosage for various scenarios has not yet been fully described in the lit- erature. However, improved clinical outcome may be associated with the use of two concurrent antibiotics compared with use of a single antibi- otic, an outcome attributed to syner- gistic elution and antibacterial ac- tions. 20,21 Exceeding a threshold of 8 g of antibiotics per 40 g of PMMA is not recommended because the me- chanical properties of the cement may be altered such that it cannot be formed and molded successfully. 23 Sustained local supratherapeutic antibiotic levels can be achieved and maintained with appropriate use of antibiotic-impregnated cement. 25 The contribution of antibiotics to mem- brane formation remains largely un- explored. Currently, it is not known whether the presence of antibiotics and the interaction of differing con- centrations and chemical makeup have an effect on membrane forma- tion. Surgical Technique Reconstruction of large bone defects using the two-stage induced mem- brane technique is straightforward but requires careful preoperative planning and attention to detail to achieve optimal results (Figure 1). In the first stage of reconstruction, thor- A, Preoperative AP radiograph of the forearm demonstrating signicant bone loss and fracture displacement secondary to high-energy trauma in a 38-year-old man. Thorough irrigation and dbridement were performed followed by open reduction and internal xation of the radius and ulna. B, Clinical photograph of the forearm demonstrating soft-tissue coverage with a free ap and split-thickness skin graft. No signs of necrotic tissue or debris were noted at the time of denitive soft-tissue coverage. C, Postoperative AP radiograph of the wrist demonstrating restoration of length and alignment. The distal radioulnar joint was pinned to address instability. A large antibiotic-impregnated cement spacer was placed into the metaphyseal defect of the distal radius. D, Postoperative AP radiograph of the wrist obtained 10 months after cement spacer removal and placement of iliac crest autograft in the induced membrane site. Full consolidation is noted at the site of the metaphyseal defect. Revision plating was undertaken at the time of grafting because loosened and broken screws were present in the distal articular fragment. Figure 1 Induced Membrane Technique for Reconstruction To Manage Bone Loss 144 Journal of the American Academy of Orthopaedic Surgeons ough and efficacious dbridement must be performed to limit the risk of subsequent infection by reducing the number of microorganisms and removing necrotic material. Ideally, complete removal of all devitalized bone and soft tissue is done at this time. This material should not be re- tained for reconstruction. The injury is then stabilized. Various methods of internal and external fixation can be used in conjunction with the in- duced membrane technique. The fix- ation construct should be stable enough to allow the soft tissues to heal before the second stage of the procedure. If possible, soft-tissue re- pair or reconstruction should be per- formed in a manner that will accom- modate the secondary (ie, bone grafting) procedure. PMMA is mixed by hand and anti- biotics added for local depot deliv- ery. When a specific offending organ- ism and its sensitivity are identified, the appropriate antibiotic is chosen. However, often the pathogen is un- known or no visible infection is pres- ent, and empiric treatment is used. Cement should be placed into the de- fect during later stages of polymer- ization to allow proper sizing and shaping of the spacer while limiting interdigitation with cancellous bone. The spacer should overlap the outer cortical ends of the remaining bone to ensure that the graft has sufficient room to heal (Figure 2). If the condi- tion of the soft tissue allows, the spacer should be larger than the orig- inal defect to permit placement of enough bone graft for reconstruction of the defect. The cement spacer can be shaped into a simple block or placed around abnormal anatomy or a fixation device, such as an in- tramedullary (IM) nail (Figure 3). We recommend temporary removal A, Intraoperative photograph demonstrating signicant femoral bone loss around an intramedullary (IM) nail secondary to a high-energy gunshot injury. B, Intraoperative photograph demonstrating placement of a cement spacer around the IM nail; the cortical ends of the bone are enveloped by the spacer to ensure that the induced membrane is created in a similar fashion. C, Postoperative AP radiograph of the distal femur demonstrating restoration of the anatomic axis of the extremity with the IM nail and the polymethyl methacrylate (PMMA) spacer. The medial split-thickness skin graft is outlined by staples. D, Postop- erative lateral radiograph of the same distal femur. Undisturbed comminuted cortical fragments are visible posterior to the PMMA spacer. Figure 2 Benjamin C. Taylor, MD, et al March 2012, Vol 20, No 3 145 of the cement spacer during the final stages of polymerization, if possible, because the exothermic reaction of PMMA curing can be significant and may lead to heat necrosis in the sur- rounding bone and soft tissue. When spacer removal is not possible, judi- cious use of saline can limit any se- quelae of heat necrosis. Definitive soft-tissue coverage and spacer place- ment should be performed during the same surgical procedure. The cement spacer should remain in place for 4 to 8 weeks to allow the membrane to fully develop biochemi- cally and physically. 13,26 However, de- layed soft-tissue healing or other pa- tient variables can delay the second stage of the procedure for several ad- ditional weeks with no significant ev- idence of membrane degrada- tion. 9,10,12 The membrane is identified and maintained, then incised care- fully to remove the cement spacer. The use of an osteotome and mallet typically is required to remove the PMMA in a piecemeal fashion (Fig- ure 4). If an IM nail is used for fixation, a second membrane forms between the cement spacer and the nail; this membrane should also be maintained to maximize healing and promote corticalization of the graft. Native cortical bone ends should then be ap- propriately freshened with curets, rongeurs, or osteotomes to improve graft incorporation to native bone. In addition, the IM canal should be opened on either end of the defect to improve local vascularity. However, if an IM nail is in place, we do not recommend nail removal or ex- change because of the potential for destabilization. Excellent results have been reported with mainte- nance of the original IM nail. 27 Cancellous autograft can be har- vested from the anterior or posterior iliac crest, but this is often associated with significant risk of donor site pain and morbidity. 2 We use and recommend the Reamer- Irrigator-Aspirator (RIA; Synthes, Westchester, PA) for femoral bone graft harvest because the biologic content of this graft has been shown to be equivalent or superior to that of iliac crest graft, with volumes of 80 mL obtainable from each fe- mur. 27,28 The biologic potential of this IM graft has also been reported in clinical studies; when used for re- construction of segmental defects, this graft has union rates equal to or better than those associated with il- iac crest graft as well as fewer re- ported complications and less donor site morbidity. 29-31 However, femoral bone graft harvest is not without morbidity; the harvest site should be selected carefully on an case-by-case basis. Cancellous autograft can be used with extenders (eg, cancellous al- lograft, demineralized bone matrix) if bone graft volume is insufficient. Extender volume of 25% of the fi- nal graft composition has been used without increasing the rate of com- plications or nonunion. 9,12 Use of other osteoinductive materials has not yet been thoroughly investigated; BMP-7 is the only adjunct that has been evaluated, and increased rates of delayed deformity and bone graft resorption have been reported with its use. 12 Additional evidence-based studies are needed before recommen- dations can be made regarding use of other osteoinductive materials. The autograft is placed into the de- fect, and the exposed ends of the na- tive bone are enveloped with the graft. Care must be taken to avoid packing a large mass of graft too tightly, especially when fixation methods other than IM nailing are used; a large mass of cancellous graft packed to cortical density will not fully revascularize or mature, leading to poor graft consolidation. 27,31 The membrane is then sutured over the inlaid bone graft, creating a closed environment (Figure 5). Outcomes In 2000, Masquelet et al 10 reported a union rate of 100% in a series of 35 patients with upper and lower ex- tremity segmental defects that mea- sured 4 to 25 cm in length. The au- thors found that the rate of bone healing did not correlate with the A, Postoperative AP radiograph demonstrating placement of a polymethyl methacrylate spacer (arrows) around an intramedullary nail to manage segmental bone loss associated with an infraisthmal fracture of the tibia in a 27-year-old man. The spacer was maintained for 10 weeks and was subsequently replaced with cancellous autograft. B, AP radiograph in the same patient 24 months after hardware removal. Complete consolidation and corticalization of the graft are noted. Figure 3 Induced Membrane Technique for Reconstruction To Manage Bone Loss 146 Journal of the American Academy of Orthopaedic Surgeons length of the defect in patients treated with induced membranes and external fixation. The mean time to full weight bearing was 8.5 months. Masquelet and Begue 12 followed this initial study with a prospective anal- ysis of 11 patients treated using the same protocol but with the addition of BMP-7. The authors reported a 91% rate of bony union in defects that measured 5 to 18 cm. BMP-7 was added to hasten formation of cortical bone, but local partial re- sorption of the graft was noted in all cases, which was an unexpected find- ing. The authors concluded that the full effect of adjunct BMP-7 could not be determined, and its use could not be recommended without addi- tional research. Other investigators have reported similar results with variations of the original technique. Stafford and Nor- ris 27 described a series of 27 lower extremity nonunions with segmental bone loss treated with RIA-harvested bone graft and either IM nailing or plate-and-screw fixation constructs. They reported a healing rate of 90% at 1-year follow-up. McCall et al 31 reported on a series of 20 patients with upper and lower extremity seg- mental bone defects treated with the induced membrane technique and fixation with either IM nails or A, Intraoperative photograph of the proximal tibia demonstrating the mature induced membrane and cement spacer at the time of spacer removal. The membrane is nonadherent to the underlying polymethyl methacrylate (PMMA) spacer. The segmental defect was spanned with a lateral locking plate. B, Intraoperative photograph demonstrating removal of the spacer in a piecemeal fashion while the induced membrane is carefully protected. The PMMA spacer often needs to be removed in this manner to limit the risk of iatrogenic injury to the membrane or surrounding tissues. C, Intraop- erative photograph demonstrating the large cavitary space created by removing the PMMA spacer. The membrane is 3 mm thick, slightly thicker than a typical induced membrane. Figure 4 Intraoperative photograph of the proximal tibia. The mature membrane was sutured to create a closed environment for graft consolidation. Plate xation is shown on top of the membrane. Figure 5 Benjamin C. Taylor, MD, et al March 2012, Vol 20, No 3 147 plate-and-screw constructs. They noted a bony union rate of 85% at final follow-up; however, seven pa- tients required additional surgery af- ter the second stage (ie, spacer re- moval and bone grafting) of the procedure. Apard et al 32 reported a bony union rate of 92% in 12 pa- tients with segmental bone loss of the tibia treated with induced mem- branes and IM nailing. Full weight bearing was permitted at 4 months because IM nails were used instead of external fixation, as described in the original technique. Injuries to the wrist and hand with segmental bone loss caused by trauma or infection have also been managed with the induced mem- brane technique. Flamans et al 33 re- ported an 82% rate of bony union with this technique and fixation with pinning or plate-and-screw con- structs. They concluded that the in- duced membrane technique is useful in the setting of severe bony and soft-tissue injuries of the hand, po- tentially avoiding acute shortening and the need for microsurgery or amputation. This technique has also been used successfully for recon- struction of devastating foot injuries, with full weight bearing permitted by 9 months postoperatively. 34,35 Despite encouraging early results, the level of evidence for this technique remains low because the current published re- ports are either retrospective case se- ries or small prospective noncompar- ative studies. Complications Infection as a result of inadequate dbridement or subsequent de novo development remains the primary complication associated with this treatment method. Masquelet and colleagues 9,10 emphasize the impor- tance of methodical, thorough d- bridement; they recommend using a spacer without antibiotics and a week-long regimen of oral antibiot- ics to avoid masking inadequate d- bridement. This treatment protocol has the advantage of revealing infec- tion early rather than after the sec- ond stage of the procedure, thus avoiding bone graft loss. Conversely, use of antibiotic-impregnated cement is well established in the orthopaedic literature; this technique, in combi- nation with adequate dbridement, has the potential to decrease infec- tion rates in the time between stages of this procedure. 36 Reported rates of septic complications leading to re- construction failure range from zero to 8%; most of these failures are at- tributed to inadequate dbride- ment. 9,12,27,31-33,35 Additional insight into infection can be obtained at the time of bone grafting; successful maintenance of bone graft and treat- ment of positive cultures with addi- tional intravenous antibiotics have been reported. 37 Delayed stress fracture is another potential complication of the in- duced membrane technique. Several cases of delayed stress fracture have been reported, occurring as late as 2 years after reconstruction. 9,32 This phenomenon seems to occur before complete corticalization of the bone, which can take several years from surgery to complete. An increased in- cidence of delayed stress fractures has been reported with use of exter- nal fixation for definitive bony stabi- lization compared with fixation with IM nails or plate-and-screw con- structs; however, head-to-head com- parison of outcomes associated with different fixation methods is lacking. Future Directions The concept of using induced mem- branes to manage septic or aseptic bone loss is fairly well established, but further research is required. Characterization of the biochemical makeup of the membrane and the optimal time frame for staging are limited. Currently, analysis of only transforming growth factor-1, BMP-2, vascular endothelial growth factor, and core-binding factor -1 has been performed. Further insight into the osteoinductive factors in- duced and the timing of their release could potentially result in improve- ments in outcomes by revealing a need for supplementation with other osteoinductive factors and by dictat- ing optimal timing of the second stage of the procedure. Timing of bone graft placement remains a topic of debate; initial biochemical analy- sis of BMP-2 points to definitive grafting at 4 weeks, but research on the secretion patterns of other coex- isting factors is lacking. 13 Much of the clinical evidence regarding timing of the second stage of the procedure is highly variable; cement removal and grafting have been performed 4 weeks to 19 months after cement im- plantation without significant evi- dence of membrane degradation. 12,32 Whether the induced membrane has osteogenic qualities also remains unknown. In animal models in which bone graft was not placed in the de- fect after cement spacer removal, de novo bone formed in the periphery of the cavity on the internal aspect of the induced membrane, which sug- gests that the membrane may contain pluripotent mesenchymal cells. 38 Soft-tissue membranes that form around joint prostheses produce prostaglandins, which are known to inhibit differentiation of osteoclast precursors. 38 The effect of prosta- glandin production has not yet been investigated. However, it may play a role in the ability of the membrane to protect against significant resorp- tion in the autograft bone. Further investigation is needed to determine whether PMMA is the ideal spacer material. Data are lack- Induced Membrane Technique for Reconstruction To Manage Bone Loss 148 Journal of the American Academy of Orthopaedic Surgeons ing regarding the optimal chemical makeup of the spacer, and it is possi- ble that an alternative substance could create a membrane that might further improve clinical outcomes. Masquelet and Begue 12 pointed out that a smooth surface, such as that produced by PMMA, leads to a smooth membrane lining. A textured spacer surface has the theoretic ad- vantage of creating a membrane with villous hyperplasia, leading to in- creased internal surface area and po- tentially increased vascularity as well as improved growth factor secretion. Analysis of bone grafts and bone graft substitutes used in the induced membrane model warrants further investigation to determine which graft will produce optimal clinical and radiographic results. Cancellous autograft harvested from the iliac crest or from IM reamings is cur- rently used, and bone substitute (eg, demineralized bone matrix) is used as an extender, if necessary. The question remains whether osteoin- ductivity and possible osteogenic properties of the induced membrane are enough to reconstitute the bony defect with use of bone extenders alone, or whether a certain ratio of autograft is necessary for incorpora- tion and healing. In one case report, morcellized cancellous autograft was augmented with a large cortical strut autograft from the contralateral tibia during the second stage of the in- duced membrane procedure; rapid incorporation of the strut was re- ported, with full cortical reconstitu- tion by 1 year postoperatively. 39 Use of cortical struts with the induced membrane technique has otherwise not been examined. It remains to be seen whether these grafts have the potential to promote earlier healing and improve early mechanical strength. Evaluation of the effect of different stabilization techniques on perioper- ative and long-term clinical out- comes is also lacking. In the initial description of the induced membrane technique, external fixators were used for limb stabilization, but other authors have noted potential difficul- ties with soft-tissue care as well as pin tract complications. 31,32 In addi- tion, stabilization of a large defect is difficult with external fixation, and if this method fails to maintain the axis of the limb, both early and delayed osteotomies may be required. 9,12 No comparative studies exist on fixation methods used with the induced mem- brane model; successful results have been reported with plate-and-screw constructs, locked IM nailing, and external fixators. Further research could provide insight into optimal construct flexibility and examine the nuances of each fixation method. When an IM nail is used, a second internal membrane forms around the exterior of the nail, potentially lead- ing to an increase in local vascularity and release of osteoinductive factors. Masquelet and Begue 12 noted that the second membrane reduces the amount of space available for bony reconstruction; however, the de- crease in bone graft volume does not seem to negatively affect clinical or radiographic outcomes, and less bone graft is needed for reconstruc- tion. Summary Management of segmental bone de- fects remains challenging and is often fraught with complications and long treatment periods. The induced membrane technique for reconstruc- tion of bone loss exhibits promising early clinical and radiographic out- comes; however, consensus and/or evidence regarding many aspects of the procedure are lacking. In studies to date, the membrane appears to eliminate local soft-tissue ingrowth into the bone defect, prevent graft re- sorption, and promote neovascular- ization and corticalization of the graft. In addition, the membrane may have osteoinductive and weak osteogenic capabilities. Early results with this technique are encouraging. This treatment method should be considered for patients with signifi- cant upper and/or lower extremity bone loss. References Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 1 is a level I study. References 4 and 17 are level II studies. References 2, 6, 12, 20, and 38 are level III studies. References 3, 5, 7-11, 13-16, 23, 25- 28, and 30-36 are level IV studies. References 29 and 39 are level V expert opinion. References printed in bold type are those published within the past 5 years. 1. Bosse MJ, MacKenzie EJ, Kellam JF, et al: An analysis of outcomes of reconstruction or amputation after leg- threatening injuries. N Engl J Med 2002; 347(24):1924-1931. 2. Ahlmann E, Patzakis M, Roidis N, Shepherd L, Holtom P: Comparison of anterior and posterior iliac crest bone grafts in terms of harvest-site morbidity and functional outcomes. J Bone Joint Surg Am 2002;84(5):716-720. 3. Hertel R, Gerber A, Schlegel U, Cordey J, Regsegger P, Rahn BA: Cancellous bone graft for skeletal reconstruction: Muscular versus periosteal bed. Preliminary report. Injury 1994;25(suppl 1):A59-A70. 4. Weiland AJ, Phillips TW, Randolph MA: Bone grafts: A radiologic, histologic, and biomechanical model comparing autografts, allografts, and free vascularized bone grafts. Plast Reconstr Surg 1984;74(3):368-379. 5. Gilmer WS Jr, Tooms RE, Salvatore JE: An experimental study of the influence of implanted polyurethane sponges upon subsequent bone formation. Surg Gynecol Obstet 1961;113:143-148. 6. Eickholz P, Pretzl B, Holle R, Kim TS: Long-term results of guided tissue regeneration therapy with non- Benjamin C. Taylor, MD, et al March 2012, Vol 20, No 3 149 resorbable and bioabsorbable barriers: III. Class II furcations after 10 years. J Periodontol 2006;77(1):88-94. 7. Meinig RP, Rahn B, Perren SM, Gogolewski S: Bone regeneration with resorbable polymeric membranes: Treatment of diaphyseal bone defects in the rabbit radius with poly(L-lactide) membrane. A pilot study. J Orthop Trauma 1996;10(3):178-190. 8. Gerber A, Gogolewski S: Reconstruction of large segmental defects in the sheep tibia using polylactide membranes: A clinical and radiographic report. Injury 2002;33(suppl 2):B43-B57. 9. Masquelet AC: Muscle reconstruction in reconstructive surgery: Soft tissue repair and long bone reconstruction. Langenbecks Arch Surg 2003;388(5): 344-346. 10. Masquelet AC, Fitoussi F, Begue T, Muller GP: Reconstruction of the long bones by the induced membrane and spongy autograft [French]. Ann Chir Plast Esthet 2000;45(3):346-353. 11. Viateau V, Bensidhoum M, Guillemin G, et al: Use of the induced membrane technique for bone tissue engineering purposes: Animal studies. Orthop Clin North Am 2010;41(1):49-56. 12. Masquelet AC, Begue T: The concept of induced membrane for reconstruction of long bone defects. Orthop Clin North Am 2010;41(1):27-37. 13. Pelissier P, Masquelet AC, Bareille R, Pelissier SM, Amedee J: Induced membranes secrete growth factors including vascular and osteoinductive factors and could stimulate bone regeneration. J Orthop Res 2004;22(1): 73-79. 14. Viateau V, Guillemin G, Bousson V, et al: Long-bone critical-size defects treated with tissue-engineered grafts: A study on sheep. J Orthop Res 2007; 25(6):741-749. 15. Viateau V, Guillemin G, Calando Y, et al: Induction of a barrier membrane to facilitate reconstruction of massive segmental diaphyseal bone defects: An ovine model. Vet Surg 2006;35(5):445- 452. 16. Freund R, Wolff TW, Freund B: Silicone block interposition for traumatic bone loss. Orthopedics 2000;23(8):795, 799, 802, 804. 17. Viateau V, Guillemin G, Yang YC, et al: A technique for creating critical-size defects in the metatarsus of sheep for use in investigation of healing of long-bone defects. Am J Vet Res 2004;65(12):1653- 1657. 18. Cui Q, Mihalko WM, Shields JS, Ries M, Saleh KJ: Antibiotic-impregnated cement spacers for the treatment of infection associated with total hip or knee arthroplasty. J Bone Joint Surg Am 2007;89(4):871-882. 19. Joseph TN, Chen AL, Di Cesare PE: Use of antibiotic-impregnated cement in total joint arthroplasty. J Am Acad Orthop Surg 2003;11(1):38-47. 20. Anagnostakos K, Kelm J, Regitz T, Schmitt E, Jung W: In vitro evaluation of antibiotic release from and bacteria growth inhibition by antibiotic-loaded acrylic bone cement spacers. J Biomed Mater Res B Appl Biomater 2005;72(2): 373-378. 21. Hanssen AD, Spangehl MJ: Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements. Clin Orthop Relat Res 2004;(427):79-85. 22. Jaeblon T: Polymethylmethacrylate: Properties and contemporary uses in orthopaedics. J Am Acad Orthop Surg 2010;18(5):297-305. 23. Hsieh PH, Chen LH, Chen CH, Lee MS, Yang WE, Shih CH: Two-stage revision hip arthroplasty for infection with a custom-made, antibiotic-loaded, cement prosthesis as an interim spacer. J Trauma 2004;56(6):1247-1252. 24. Kuehn KD, Ege W, Gopp U: Acrylic bone cements: Mechanical and physical properties. Orthop Clin North Am 2005; 36(1):29-39, v-vi. 25. Masri BA, Duncan CP, Beauchamp CP: Long-term elution of antibiotics from bone-cement: An in vivo study using the prosthesis of antibiotic-loaded acrylic cement (PROSTALAC) system. J Arthroplasty 1998;13(3):331-338. 26. Klaue K, Knothe U, Anton C, Masquelet AC, Perren S: Biological implementation of autologous foreign body membranes in consolidation of massive cancellous bone grafts. J Bone Joint Surg Am 1997; 79(suppl II):236. 27. Stafford PR, Norris BL: Reamer- irrigator-aspirator bone graft and bi Masquelet technique for segmental bone defect nonunions: A review of 25 cases. Injury 2010;41(suppl 2):S72-S77. 28. Schmidmaier G, Herrmann S, Green J, et al: Quantitative assessment of growth factors in reaming aspirate, iliac crest, and platelet preparation. Bone 2006; 39(5):1156-1163. 29. Pape HC, Tarkin IS: Reamer irrigator aspirator: A new technique for bone graft harvesting from the intramedullary canal. Oper Tech Orthop 2008;19:108- 113. 30. Lowe JA, Della Rocca GJ, Murtha Y, et al: Complications associated with negative pressure reaming for harvesting autologous bone graft: A case series. J Orthop Trauma 2010;24(1):46-52. 31. McCall TA, Brokaw DS, Jelen BA, et al: Treatment of large segmental bone defects with reamer-irrigator-aspirator bone graft: Technique and case series. Orthop Clin North Am 2010;41(1):63- 73. 32. Apard T, Bigorre N, Cronier P, Duteille F, Bizot P, Massin P: Two-stage reconstruction of post-traumatic segmental tibia bone loss with nailing. Orthop Traumatol Surg Res 2010;96(5): 549-553. 33. Flamans B, Pauchot J, Petite H, et al: Use of the induced membrane technique for the treatment of bone defects in the hand or wrist, in emergency [French]. Chir Main 2010;29(5):307-314. 34. Huffman LK, Harris JG, Suk M: Using the bi-masquelet technique and reamer- irrigator-aspirator for post-traumatic foot reconstruction. Foot Ankle Int 2009;30(9):895-899. 35. Pelissier P, Bollecker V, Martin D, Baudet J: Foot reconstruction with the bi-Masquelet procedure [French]. Ann Chir Plast Esthet 2002;47(4):304-307. 36. Sancineto CF, Barla JD: Treatment of long bone osteomyelitis with a mechanically stable intramedullar antibiotic dispenser: Nineteen consecutive cases with a minimum of 12 months follow-up. J Trauma 2008;65(6): 1416-1420. 37. Forsberg JA, Potter BK, Cierny G III, Webb L: Diagnosis and management of chronic infection. J Am Acad Orthop Surg 2011;19(suppl 1):S8-S19. 38. Klaue K, Knothe U, Anton C, et al: Bone regeneration in long-bone defects: Tissue compartmentalisation? In vivo study on bone defects in sheep. Injury 2009; 40(suppl 4):S95-S102. 39. Biau DJ, Pannier S, Masquelet AC, Glorion C: Case report: Reconstruction of a 16-cm diaphyseal defect after Ewings resection in a child. Clin Orthop Relat Res 2009;467(2):572-577. Induced Membrane Technique for Reconstruction To Manage Bone Loss 150 Journal of the American Academy of Orthopaedic Surgeons