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The choice between allograft or demineralized bone matrix is not unambiguous in trauma surgery

Open AccessPublished:November 06, 2020DOI:https://doi.org/10.1016/j.injury.2020.11.013

      Highlights

      • Allografts and demineralised bone matrix are widely used for fracture surgery.
      • This study evaluated the difference between allogeneic allograft or DBM as a bone substitute in trauma surgery.
      • The efficacy, clinical evidence, safety, cost, and patient acceptance were evaluated.
      • It is not possible to definitively conclude whether it makes a difference if allograft or DBM is used in trauma surgery.
      • This article informs the surgeons choice of allograft or DBM.

      Abstract

      In fracture surgery, large bone defects and non-unions often require bone transplantation, and alternatives to autograft bone substitutes in the form of allografts from bone banks and the derivate demineralised bone matrix (DBM) are widely used. With a focus on efficacy, clinical evidence, safety, cost, and patient acceptance, this review evaluated the difference between allogeneic allograft or DBM as a bone substitute in trauma surgery. The efficacy in supporting bone healing from allograft and DBM is highly influenced by donor characteristics and graft processing. Mechanical stability is achieved from a structural graft. Based on the existing literature it is difficult to identify where DBM is useful in trauma surgery, and the level of evidence for the relevant use of allograft bone in trauma is low. The risk of transmitting diseases is negligible, and the lowest risk is from DBM due to the extensive processing procedures. A cost comparison showed that DBM is significantly more expensive. The experiences of dental patients have shown that many patients do not want to receive allografts as a bone substitute. It is not possible to definitively conclude whether it makes a difference if allograft or DBM is used in trauma surgery. It is ultimately the surgeon's individual choice, but this article may be useful in providing considerations before a decision is made.

      Keywords

      Introduction

      Fracture surgery is regularly challenged by the presence of bone defects, reduced mechanical stability, and a lack of bone healing, wherein bone substitutes can be useful. Bone autograft is the gold standard, but has side effects from donor sites and is less useful when there is a need for larger amounts [
      • Bostrom MPG
      • Seigerman DA.
      The Clinical Use of Allografts, Demineralized Bone Matrices, Synthetic Bone Graft Substitutes and Osteoinductive Growth Factors: A Survey Study.
      ,
      • Lomas R
      • Chandrasekar A
      • Board TN
      Bone allograft in the UK : perceptions and realities.
      ]. The alternatives are allograft and demineralised bone matrix (DBM), where there are no similar limitations in volume and no association with the same comorbidities as autograft [
      • Gruskin E
      • Doll BA
      • Futrell FW
      • Schmitz JP
      • Hollinger JO
      Demineralized bone matrix in bone repair : history and use ☆.
      ]. Allograft bone is harvested from an individual different from the recipient, and DBM is a commercial and processed derivate from allograft bone [
      • Gruskin E
      • Doll BA
      • Futrell FW
      • Schmitz JP
      • Hollinger JO
      Demineralized bone matrix in bone repair : history and use ☆.
      ].
      The treatment of bone defects with bone grafting has been known for several hundreds of years. From the literature, the first known bone transplant was performed in 1668, when Job van Meekeren, a Dutch surgeon, used a bone fragment (xenograft) from a dead dog to repair a defect in a soldier's skull [
      • Donati D
      • Zolezzi C
      • Tomba P
      • Viganò A
      Bone grafting: Historical and conceptual review, starting with an old manuscript by Vittorio Putti.
      ,
      • van Meekeren J.
      Heelen geneeskonstige aanmerkingen.
      ]. The use of allograft was first described in 1879, when the Scottish surgeon William MacEwen took a tibia from a child with rickets and transplanted it into another boy [
      • Macewen W.
      Observations concerning transplantation of bone. Illustrated by a case of inter-human osseous transplantation, whereby over two-thirds of the shaft of a humerus was restored.
      ].
      Ten years later, Senn used decalcified bone as a bone substitute to treat bone defects [
      • Senn N.
      On the healing of aseptic bone cavities by implantation of antiseptic decalcified bone.
      ]. Following the success of experimental studies with 14 dogs, he did clinical observations in humans. His first case was a 35-year-old male who had osteomyelitis in the tibia and a large bone defect which was filled with chips of decalcified bone. The entire procedure was done without any anaesthesia, as the patient refused ether or chloroform.
      The processing and decalcification of allograft bone to make DBM was later systematically described by Marshall Urist in 1965; he explained the presence of bone morphogenic protein (BMP) to be responsible for bone formation [
      • Urist MR.
      Bone : Formation by Autoinduction.
      ]. Later other growth factors were identified [
      • Wozney JM
      • Rosen V
      • Celeste AJ
      • Mitsock LM
      • Whitters MJ
      • Kriz RW
      • et al.
      Novel regulators of bone formation: Molecular clones and activities.
      ]. In 1991, the first commercial DBM products became available. Significant arguments for using DBM instead of autograft or allograft bone are that the risk of disease transmission is eliminated and there are no quantity limitations. Today, bone substitutes are widely used, and a national survey from bone banks in the USA reveals that 2.5 million different bone grafts were distributed in 2015, which was an increase of 38% since 2012 [

      US Department of Health and Human Services. The 2012 and 2015 National Tissue Recovery through Utilization Survey Report 2015:1–95.

      ].
      A study from The Hospital for Special Surgery in New York analysed the use of different graft products in 2002-2004 [
      • Bostrom MPG
      • Seigerman DA.
      The Clinical Use of Allografts, Demineralized Bone Matrices, Synthetic Bone Graft Substitutes and Osteoinductive Growth Factors: A Survey Study.
      ]. It was found that 19% of all bone substitutes used at the hospital were related to trauma surgery, of which 10% were allograft bone and 82% were DBM products [
      • Bostrom MPG
      • Seigerman DA.
      The Clinical Use of Allografts, Demineralized Bone Matrices, Synthetic Bone Graft Substitutes and Osteoinductive Growth Factors: A Survey Study.
      ]. Based on this statistic, DBM appears to be a primary choice rather than allograft bone.
      The diversity of DBM products in various forms, and the uncertainty of the indications and efficacy, can be confusing for the clinician. This raises the question in this minireview: with a focus on efficacy, clinical evidence, safety, cost, and patient acceptance, is there a difference if we use allogeneic allograft or DBM as a bone substitute in trauma surgery?
      A literature search was performed in databases from PubMed, EMBASE and Google Scholar until January 2020. Keywords “allograft”, “bonegraft”, “DBM” and “Demineralized Bone Matrix” were used in combination with either “fracture”, “efficacy”, “clinical”, “safety”, “complication”, “cost” or “patient acceptance”. In Pubmed MeSH Search terms was used to narrow the number of papers. Studies were limited to papers published in English language and for clinical use were only papers related to trauma and fracture surgery selected.

      Processing

      Processing allograft bone

      To understand the differences between allograft and DBM, it is necessary to explore the differences in the origin and processing procedures. Allograft is derived from both living and deceased donors; that used for commercial DBM only originates from deceased donors. After harvesting, the graft is typically sent to a bone bank for further handling. Allograft can be divided into fresh or frozen and structurally cancellous or cortical. Fresh allograft must be used shortly after harvesting, while frozen allograft is stored in a bone bank for later use [
      • Taylor DW
      • Bohm KC
      • Taylor JE
      • Gross AE
      Use of fresh osteochondral allograft in repair of distal femur after trauma.
      ].
      Before storage, allograft may undergo different kinds of preparation such as debridement with removal of bone marrow, cleaning and disinfection procedures, cryopreservation, and irradiation.
      In many countries, including the UK, frozen femoral heads from living donors are delivered to the operating room unprocessed [
      • Lomas R
      • Chandrasekar A
      • Board TN
      Bone allograft in the UK : perceptions and realities.
      ].

      Processing DBM

      DBM is an allograft bone that has gone through a standardised process as described by Urist [
      • Urist MR.
      Bone : Formation by Autoinduction.
      ]. Cortical bone from long bones is first pulverised and then decalcified by soaking it in an acid solution. During this process all the mineral components are removed and the remaining product of collagen bone matrix, growth factors and non-collagenous proteins, and processed DBM do not contain any viable cells [
      • Gruskin E
      • Doll BA
      • Futrell FW
      • Schmitz JP
      • Hollinger JO
      Demineralized bone matrix in bone repair : history and use ☆.
      ]. The processing of commercial DBM may vary between manufacturers, with differences in the acidic solutions used, length of demineralisation, temperature, and other procedures including disinfection and radiation [
      • Gruskin E
      • Doll BA
      • Futrell FW
      • Schmitz JP
      • Hollinger JO
      Demineralized bone matrix in bone repair : history and use ☆.
      ,
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ]. The initial DBM product is a powder but, as powder can be difficult to handle and has a tendency to migrate from the graft site, manufacturers try to solve these problems by adding different carriers [

      Zhang H, Yang L, Yang X, Wang F, Feng J, Hua K. Demineralized Bone Matrix Carriers and their Clinical Applications : An Overview. Orthp Surg 2019:725–37. 10.1111/os.12509.

      ]. The type of carriers varies between manufacturers and the final product can have different forms such as putty, gel, strips, pellets, blocks, and granules [
      • Gruskin E
      • Doll BA
      • Futrell FW
      • Schmitz JP
      • Hollinger JO
      Demineralized bone matrix in bone repair : history and use ☆.
      ,

      Zhang H, Yang L, Yang X, Wang F, Feng J, Hua K. Demineralized Bone Matrix Carriers and their Clinical Applications : An Overview. Orthp Surg 2019:725–37. 10.1111/os.12509.

      ].

      Efficacy

      To explain the variation in the efficacy of DBM and bone bank allograft it helps to look at the principles of fracture healing. Giannoudis introduced the diamond concept and explained how healing is influenced by several factors from the graft and host [
      • Giannoudis P V
      • Einhorn TA
      • Marsh D
      Fracture healing : The diamond concept.
      ,
      • Andrzejowski P
      • Giannoudis P V
      The ‘ diamond concept ’ for long bone non - union management.
      ]. The concept consists of six elements essential for bone healing: 1) osteogenesis, 2) osteoconductive scaffolds, 3) osteoinductive mediators, 4) mechanical support, 5) adequate vascularity, and 6) specific host factors.
      Osteogenesis is the process of new bone formation generated by cells in the graft or host. As allograft and DBM contain no living cells there is no osteogenic effect. Osteoconduction is the process when the graft acts as a scaffold for the ingrowth of vessels, followed by resorption and new bone formation from the edges [
      • Khan SN
      • Cammisa FPJ
      • Sandhu HS
      • Diwan AD
      • Girardi FP
      • Lane JM
      The biology of bone grafting.
      ]. Osteoinduction is the process by which different proteins, such as BMP and other growth factors, are released from the donor material and stimulate recruited stem cells to differentiate into bone formatting cells.

      Efficacy from allograft bone

      The benefits of allograft are primarily gained from the osteoconductive effect, when it acts as a scaffold, and from the mechanical support. The osteoconductive effect is better achieved from cancellous allograft than from cortical grafts, because it is faster and completely incorporated [
      • Khan SN
      • Cammisa FPJ
      • Sandhu HS
      • Diwan AD
      • Girardi FP
      • Lane JM
      The biology of bone grafting.
      ]. The osteoinductive activity of allograft is dependent on the content of growth factors. This is low or has great variety in frozen allograft, and is highly influenced by the donor and the preparation of the graft material [
      • Wildemann B
      • Kadow-Romacker A
      • Pruss A
      • Haas NP
      • Schmidmaier G
      Quantification of growth factors in allogenic bone grafts extracted with three different methods.
      ,
      • Blokhuis TJ
      • Arts JJC.
      Bioactive and osteoinductive bone graft substitutes : definitions, facts and myths.
      ]. Theoretically, fresh and unprocessed allograft has the highest osteoinductive potential.

      Efficacy from DBM

      Depending on the form of the DBM, it may have an osteoconductive effect while the mechanical support is inferior. When it comes to osteoinductive potential, theoretically, DBM has a higher potential than allograft. The effect is primarily determined by the content of remaining growth factors after processing which may, unfortunately, be lowered due to processing, sterilisation, storage, and may also be related to the donor [

      Zhang H, Yang L, Yang X, Wang F, Feng J, Hua K. Demineralized Bone Matrix Carriers and their Clinical Applications : An Overview. Orthp Surg 2019:725–37. 10.1111/os.12509.

      ,
      • Wang W
      • Yeung KWK.
      Bone grafts and biomaterials substitutes for bone defect repair : A review.
      ].
      When carriers are added to the commercial products, DBM fraction are lowered, and with less DBM then are less growth factors present, meaning efficacy is reduced. The percentage of DBM by weight of product may vary from 17% in Grafton DBM and up to 100% DBM in Accell TBM, a product that is without carriers [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ,
      • van der Stok J
      • Hartholt KA
      Schoenmakers, DAL;Arts J.
      The available evidence on demineralised bone matrix in trauma and orthopaedic surgery.
      ].
      Concentration of BMP may vary between lots of the same product, and between different products [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ,
      • Zhang H
      • Yang L
      • Yang XG
      • Wang F
      • Feng JT
      • Hua KC
      • et al.
      Demineralized Bone Matrix Carriers and their Clinical Applications: An Overview.
      ]. The same batch number of a DBM product indicates that all bone material originates from the same donor and, as manufacturers are not allowed to mix bone from different donors, explains the heterogeneity of outcomes from the same products and manufacturers [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ,
      FDA (Food and Drug Administration)
      Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue- Based Products: Minimal Manipulation and Homologous Use.
      ,
      • Kinney RC
      • Ziran BH
      • Hirshorn K
      • Schlatterer D
      • Ganey T
      Demineralized Bone Matrix for Fracture Healing : Fact or Fiction ?.
      ]. The theoretical differences in efficacy from allograft and DBM are summarised in Table 1.
      Table 1Theoretically bone healing properties from the use of allograft bone and DBM in trauma
      • Khan SN
      • Cammisa FPJ
      • Sandhu HS
      • Diwan AD
      • Girardi FP
      • Lane JM
      The biology of bone grafting.
      ,
      • Wang W
      • Yeung KWK.
      Bone grafts and biomaterials substitutes for bone defect repair : A review.
      ,
      • Baldwin P
      • Li DJ
      • Auston DA
      • Mir HS
      • Yoon RS
      • Koval KJ
      Autograft, Allograft, and Bone Graft Substitutes : Clinical Evidence and Indications for Use in the Setting of Orthopaedic Trauma Surgery.
      .
      Structural allograftParticulate allograftDBM
      Osteogenesis---
      Osteoconduction+++
      Osteoinduction-+++
      Mechanical support+++--
      When companies claim they test their products for osteoinductivity, it may be difficult to interpret and compare findings with other products and vendors, as there is no consensus of testing methods. In addition, the Food and Drug Administration (FDA) in the USA categorises most DBM products as medical devices, for which there is no legal documentation requirement [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ,
      • Wildemann B
      • Kadow-Romacker A
      • Pruss A
      • Haas NP
      • Schmidmaier G
      Quantification of growth factors in allogenic bone grafts extracted with three different methods.
      ,
      • Kinney RC
      • Ziran BH
      • Hirshorn K
      • Schlatterer D
      • Ganey T
      Demineralized Bone Matrix for Fracture Healing : Fact or Fiction ?.
      ]. Most methods which test the efficacy of DBM are animal models. However, it is one thing to test how DBM works in models but another to test the clinical effect. Here again, it is necessary to recall the diamond model, where several factors must be optimally present [
      • Giannoudis P V
      • Einhorn TA
      • Marsh D
      Fracture healing : The diamond concept.
      ,
      • Andrzejowski P
      • Giannoudis P V
      The ‘ diamond concept ’ for long bone non - union management.
      ]. When using both allograft and DBM, it may be difficult to distinguish between the significance of the osteoconductive and osteoinductive factors. At the same time, the selection of patients can be of great importance, as local factors affect the ability to form bone.
      The clinician's indication for using bone substitute, the choice of substitute, and the choice of the recipient all have an impact on the outcome [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ]. There are also the unknown factors from the donor. Experiences from the clinic and from controlled studies are thus important. In trauma surgery, the evidence from existing studies for the use of allograft and DBM remains low [
      • van der Stok J
      • Hartholt KA
      Schoenmakers, DAL;Arts J.
      The available evidence on demineralised bone matrix in trauma and orthopaedic surgery.
      ,
      • Kinney RC
      • Ziran BH
      • Hirshorn K
      • Schlatterer D
      • Ganey T
      Demineralized Bone Matrix for Fracture Healing : Fact or Fiction ?.
      ].

      Indications and clinical evidence

      Indications and clinical evidence to use allograft bone

      The vast majority of allografts used in trauma are frozen and typically used as either structural graft or as non-structural particulate allograft (Fig. 1). The timing of bone grafting in trauma surgery is controversial and may be influenced by what is needed. Egol et al. list three options of ideal timing of bone grafting in trauma surgery: immediate, subacute, and delayed [
      • Egol KA
      • Nauth A
      • Lee M
      • Pape HC
      • Watson JT
      • Borrelli J
      Bone grafting: sourcing, timing, strategies, and alternatives.
      ]. If the indication for grafting is mechanical stability or the augmentation of a metaphyseal defect in load bearing bones, then bone graft is frequently used in conjunction with acute fracture fixation. With acute fractures the tissue is damaged with compromised vascularity and a raised inflammatory response, a factor which may have a negative impact on fracture healing and the acceptance of bone substitutes [
      • Andrzejowski P
      • Giannoudis P V
      The ‘ diamond concept ’ for long bone non - union management.
      ,
      • Kinney RC
      • Ziran BH
      • Hirshorn K
      • Schlatterer D
      • Ganey T
      Demineralized Bone Matrix for Fracture Healing : Fact or Fiction ?.
      ,
      • Egol KA
      • Nauth A
      • Lee M
      • Pape HC
      • Watson JT
      • Borrelli J
      Bone grafting: sourcing, timing, strategies, and alternatives.
      ]. When treating traumatic large bone defects the current trend is toward delayed bone grafting and to wait at least 6-8 weeks until the surrounding tissue is revascularized and stable. [
      • Kinney RC
      • Ziran BH
      • Hirshorn K
      • Schlatterer D
      • Ganey T
      Demineralized Bone Matrix for Fracture Healing : Fact or Fiction ?.
      ,
      • Egol KA
      • Nauth A
      • Lee M
      • Pape HC
      • Watson JT
      • Borrelli J
      Bone grafting: sourcing, timing, strategies, and alternatives.
      ].
      Fig. 1
      Fig. 1Particulate allograft used in conjunction with open reduction internal fixation of intraarticular calcaneus fracture.
      The evidence for the use of fresh allograft in trauma is very limited and primarily exists as case reports of patients with a traumatic loss of articular segments [
      • Taylor DW
      • Bohm KC
      • Taylor JE
      • Gross AE
      Use of fresh osteochondral allograft in repair of distal femur after trauma.
      ]. Several clinical studies have been published regarding the use of structural grafts in fracture surgery, but these are commonly case series and have a low level of evidence. Biermann et al. identified 15 clinical studies using structural bone graft as an augmentation of plate fixation of proximal humeral fractures, and 14 of these were a case series [
      • Biermann N
      • Prall WC
      • Böcker W
      • Mayr HO
      • Haasters F
      Augmentation of plate osteosynthesis for proximal humeral fractures: a systematic review of current biomechanical and clinical studies.
      ]. Although the evidence was low, the authors concluded that patients augmented with structural bone grafts had a higher rate of fracture healing and satisfaction than those without. Baldwin et al. came to similar conclusions, that fibular strut grafts can be used as fixation augments and also as a reduction tool in fractures, but the evidence is limited, and the “decision should be made by the treating surgeon on an individual case basis” [
      • Baldwin P
      • Li DJ
      • Auston DA
      • Mir HS
      • Yoon RS
      • Koval KJ
      Autograft, Allograft, and Bone Graft Substitutes : Clinical Evidence and Indications for Use in the Setting of Orthopaedic Trauma Surgery.
      ].
      Particulate allograft is typically used in trauma to fill metaphyseal defects, treat non-unions, and as graft extender. A review paper by Goff et al. evaluated different bone graft substitutes in the management of proximal tibial fractures and found only two studies using bank allograft, both of which were a level IV cases series with small numbers [
      • Goff T
      • Kanakaris NK
      • Giannoudis P V
      Use of bone graft substitutes in the management of tibial plateau fractures.
      ]. The overall results were good, with a high union rate and low rates of secondary collapse.

      Indications and clinical evidence to use DBM

      The indications for the use of DBM in trauma settings seem to differ between the manufacturers and those proven in clinical use. The recommended use from vendors of DBM products in relation to trauma vary from non-unions, long bone fractures, segmental defects, condylar defects, tibial plateau, pilon, talus, calcaneal, distal radius, scaphoid, and supracondylar fractures []. However, the available clinical evidence in relation to any of these indications is very limited.
      In 2015, Drosos et al. published a systematic review of the use of DBM in the extremities. They identified one level II study and two level III clinical studies in relation to long bone fractures, and one level III and three level IV studies regarding non-unions [
      • Drosos GI
      • Touzopoulos P
      • Ververidis A
      • Tilkeridis K
      • Kazakos K
      Use of demineralized bone matrix in the extremities.
      ]. The authors concluded that, according to the existing literature, there is insufficient evidence to recommend the use of DBM in fractures. Two years later, van der Stok et al. performed a similar review with an overlap of studies evaluated by Drosos [
      • van der Stok J
      • Hartholt KA
      Schoenmakers, DAL;Arts J.
      The available evidence on demineralised bone matrix in trauma and orthopaedic surgery.
      ]. Stok et al. found that DBM had been mostly used as a graft extender mixed with additional autograft or allograft, and most studies were of poor quality. The authors concluded that the evidence supporting the use of DBM in trauma is low, and it is not possible to point out any specific indications where DBM products have added value in trauma [
      • van der Stok J
      • Hartholt KA
      Schoenmakers, DAL;Arts J.
      The available evidence on demineralised bone matrix in trauma and orthopaedic surgery.
      ]. A summary of the indications for the use of allograft bone and DBM in trauma surgery is listed in Table 2. All the indications are relative and based on low levels of evidence.
      Table 2Indications for allograft and DBM use in trauma surgery.
      Structural allograftParticulate allograftDBM
      Metaphyseal bony defects-++
      Long bone defects+-/+-/+
      Fracture nonunion-++
      Graft extender-++
      Mechanical support+--

      Safety

      Any tissue from a donor has a potential risk to transmit bacteria, virus, fungi, prions, and malignant cells to the recipient [
      • McAllister DR
      • Joyce MJ
      • Mann BJ
      • Vangsness CT
      Allograft update: the current status of tissue regulation, procurement, processing, and sterilization.
      ,
      • Reikerås O
      • Reinholt FP
      • Zinöcker S
      • Shegarfi H
      • Rolstad B
      Healing of long-term frozen orthotopic bone allografts is not affected by MHC differences between donor and recipient.
      ]. Other relevant risks are the immunological response from the recipient against the graft and allergic reactions [
      • Hinsenkamp M
      • Muylle L
      • Eastlund T
      • Fehily D
      • Noël L
      • Strong DM
      Adverse reactions and events related to musculoskeletal allografts: Reviewed by the World Health Organisation Project NOTIFY.
      ].

      Safety of allograft bone

      Screening of the donor is the first step to reduce pathogen transmission, and processing done according to protocols and national and international directives is the second [
      • Lomas R
      • Chandrasekar A
      • Board TN
      Bone allograft in the UK : perceptions and realities.
      ,
      AATB. Guidance Document.
      ]. The donors not excluded based on medical history are virology screened for HIV, hepatitis B & C, HTLV, and syphilis. Local protocols may include further serological tests. Depending upon the type of tests used, there is a potential risk of not identifying the early stages of infection until a later retest is performed. After donor approval, the graft is released from quarantine and either used as a fresh-frozen allograft, like a femoral head, or processed further.
      Lomas states the two principal reasons for processing are to make the graft more effective and for safety [
      • Lomas R
      • Chandrasekar A
      • Board TN
      Bone allograft in the UK : perceptions and realities.
      ]. The processing of allograft bone can include debridement with removal of bone marrow, cleaning, disinfection, cryopreservation, and irradiation. Processed and unprocessed allograft are freeze-stored at temperatures varying between -20°C and -80°C until further use [
      • Fölsch C
      • Mittelmeier W
      • Bilderbeek U
      • Timmesfeld N
      • Von Garrel T
      • Matter HP
      Effect of storage temperature on allograft bone.
      ]. Freezing it does not guarantee the prevention of disease transmission, but it may prevent bacteria, fungi, and virus from growing [

      Moucha CS, Renard RL, Gandhi A, Lin SS, Tuan RS. Bone Allograft Safety and Performance. Eng Funct Skelet Tissues 2007:46–54. 10.1007/978-1-84628-366-6_3.

      ].
      The harvesting and processing of allograft exposes the bone to a risk of environmental contamination, which is why terminal sterilisation with gamma irradiation after the bone has been processed, sealed, and packed, is recommended [
      • Lomas R
      • Chandrasekar A
      • Board TN
      Bone allograft in the UK : perceptions and realities.
      ,
      • Taylor DW
      • Bohm KC
      • Taylor JE
      • Gross AE
      Use of fresh osteochondral allograft in repair of distal femur after trauma.
      ]. Despite careful processing procedures that eliminate bacteria, virus, and fungi, there no is sterilisation method that kill prions and no serological test to identify an infected donor.
      The highest risk of disease transmission is from fresh allograft that must be implanted within 4 days after recovery. With this use, there is no time for comprehensive donor screening and prior serological or bacterial testing, and the indications to use fresh allograft graft in trauma surgery are unknown. The second highest risk is from frozen and unprocessed grafts. In many countries, frozen femoral heads from living donors are provided as unprocessed. The surgeon can decide to process the allograft immediately prior to surgery by debridement, morselising, and sterilisation procedures, before implantation [
      • Lomas R
      • Chandrasekar A
      • Board TN
      Bone allograft in the UK : perceptions and realities.
      ].
      Allograft transplantation can cause both inflammation and antigen-dependent immunological responses. Clinically, it is difficult to distinguish between the two kinds of reactions, and both can result in rejection of the allograft. Inflammation can be the caused by bacterial or fungal infections. [
      • McAllister DR
      • Joyce MJ
      • Mann BJ
      • Vangsness CT
      Allograft update: the current status of tissue regulation, procurement, processing, and sterilization.
      ].
      Unlike other tissue transplants, allograft bone is used without any compatibility testing with the recipient. When blood, bone marrow, and other tissues are removed from the bone, it reduces the risk of reactions. Freezing procedures leave the graft without any viable cells and can contain degraded fragments that represent potential immunogenic proteins, which can theoretically cause an immunological reaction and explain rejection of the allograft [
      • Reikerås O
      • Reinholt FP
      • Zinöcker S
      • Shegarfi H
      • Rolstad B
      Healing of long-term frozen orthotopic bone allografts is not affected by MHC differences between donor and recipient.
      ,
      • Costain DJ
      • Crawford RW.
      Fresh-frozen vs. irradiated allograft bone in orthopaedic reconstructive surgery.
      ]. The clinical significance of immunological responses against allografts in trauma surgery is not yet clearly understood [
      • Reikerås O
      • Reinholt FP
      • Zinöcker S
      • Shegarfi H
      • Rolstad B
      Healing of long-term frozen orthotopic bone allografts is not affected by MHC differences between donor and recipient.
      ].
      The true incidence of infection following allograft transplantation is unknown. Infection may present with signs like local erythema, pain, purulence, unexplained systemic symptoms, and rejection of the graft. A survey by The American Association of Tissue Banks (AATB) collected data from accredited tissue banks in the USA found an overall incidence of allograft related infections of 0.014% [
      • McAllister DR
      • Joyce MJ
      • Mann BJ
      • Vangsness CT
      Allograft update: the current status of tissue regulation, procurement, processing, and sterilization.
      ]. The incidence was calculated from the distribution of 1.35 million grafts, of which 35% were bone grafts. Bacterial contamination was found in 8.1% of 270 bone allografts from 53 non-living and multiorgan donors [
      • Segur JM
      • Suso S
      • García S
      • Combalía A
      • Ramón R
      Bone allograft contamination in multiorgan and tissue donors.
      ]. A study including 401 bone donors demonstrated that 13% of femoral heads from living donors were contaminated with bacteria, including 13% of grafts from multiorgan donors and 35% from cadaveric donors [
      • Journeaux SF
      • Johnson N
      • Bryce SL
      • Friedman SJ
      • Sommerville SMM
      • Morgan D
      Bacterial contamination rates during bone allograft retrieval.
      ]. A frequently cited paper by Lord et al. reported an infection rate of 11.7% in 283 patient who received transplants of massive grafts of cadaveric bone. However, the recipient population was perhaps not representative in relation to trauma, as the indications for transplant were aggressive benign tumour or bone sarcoma [
      • Lord CF
      • Gebhardt MC
      • Tomford WW
      • Mankin HJ
      Infection in bone allografts. Incidence, nature and treatment.
      ]. The infection rate was markedly lower, at 2.6%, in a large register study including more than 1.2 million cases of allograft transplantation with associated risk factors of infection in older and comorbid patients [
      • Lee FH
      • Shen PC
      • Jou IM
      • Li CY
      • Hsieh JL
      A Population-Based 16-Year Study on the Risk Factors of Surgical Site Infection in Patients after Bone Grafting: A Cross-Sectional Study in Taiwan.
      ].
      The transmission of bacteria from allograft may not be the only explanation of postsurgical signs of infection [
      • Wu C
      • Hsieh P
      • Fan Jiang J
      • Shih H
      • Chen C
      • Hu C
      A positive bacterial culture from allograft bone at implantation does not correlate with subsequent surgical site infection.
      ]. In a study by Kappe et al., bacterial infections were seen in 6.9% of patients following allogenic bone transplantation, but after review of the clinical findings, none were likely caused by the bone graft [

      Kappe T, Cakir B, Mattes T, Reichel H, Flören M. Infections after bone allograft surgery : a prospective study by a hospital bone bank using frozen femoral heads from living donors. Cell Tissue Bank 2010:253–9. 10.1007/s10561-009-9140-5.

      ]. Recipients in trauma-related bone grafting have several risk factors for infections, such as severe tissue damage and hypoxia following acute trauma, and non-union, which may be associated with chronic infection [
      • Mills L
      • Tsang J
      • Hopper G
      • Keenan G
      • Simpson AHRW
      The multifactorial aetiology of fracture nonunion and the importance of searching for latent infection.
      ,
      • Struijs PAA
      • Poolman RW
      • Bhandari M
      Infected nonunion of the long bones.
      ]. There is a need to demonstrate by comparative bacterial typing and DNA sequencing that the infection is actually caused from contamination of the allograft [
      • Hinsenkamp M
      • Muylle L
      • Eastlund T
      • Fehily D
      • Noël L
      • Strong DM
      Adverse reactions and events related to musculoskeletal allografts: Reviewed by the World Health Organisation Project NOTIFY.
      ].
      Simonds et al. reviewed all organ tissue transplants in the USA from 1982 through 1991 and identified four cases of HIV transmission from fresh-frozen bone, and three of the four recipients became infected with HIV [
      • Simonds RJ
      • Holmberg SD
      • Hurwitz RL
      • Coleman TR
      • Bottenfield S
      • Conley LJ
      • Kohlenberg SH
      • Castro KG
      • Dahan BA
      • Schable CA
      • Rayfield MA
      • Rogers M
      Transmission of human immunodeficiency virus type 1 from a seronegative organ and tissue donor.
      ]. A project led by the World Health Organization (WHO) later identified another eight cases of HIV transmission from allograft bone [
      • Hinsenkamp M
      • Muylle L
      • Eastlund T
      • Fehily D
      • Noël L
      • Strong DM
      Adverse reactions and events related to musculoskeletal allografts: Reviewed by the World Health Organisation Project NOTIFY.
      ]. Four of the total twelve cases were HIV transmitted from cryopreserved bone, five from frozen femoral heads or patellae, and two from bone chips. All HIV transmissions, except one from an untested donor in 1996, occurred between 1984 and 1986 [
      • Hinsenkamp M
      • Muylle L
      • Eastlund T
      • Fehily D
      • Noël L
      • Strong DM
      Adverse reactions and events related to musculoskeletal allografts: Reviewed by the World Health Organisation Project NOTIFY.
      ]. The same WHO study reported ten cases of hepatitis C virus (HCV) transmissions, all coming from frozen or cryopreserved allograft that had not been heavily processed or sterilised. The latest reported case was in 2000 [
      • Hinsenkamp M
      • Muylle L
      • Eastlund T
      • Fehily D
      • Noël L
      • Strong DM
      Adverse reactions and events related to musculoskeletal allografts: Reviewed by the World Health Organisation Project NOTIFY.
      ]. Transmission of Epstein-Barr virus, cytomegalovirus, West Nile virus, or Creutzfeldt-Jacobs disease has not yet been reported in relation to bone transplantation [
      • Hinsenkamp M
      • Muylle L
      • Eastlund T
      • Fehily D
      • Noël L
      • Strong DM
      Adverse reactions and events related to musculoskeletal allografts: Reviewed by the World Health Organisation Project NOTIFY.
      ].
      Today, the risk of transmission is markedly reduced by comprehensive screening procedures where most donors with potential risks are excluded. This is supported by findings from the UK, where the evaluation of serological tests from 34750 living and pre-screened donors over a 10 year period revealed an incidence of positive tests for viral pathogens in less than one of every 1500 tests; none were positive for HIV [
      • Lomas R
      • Chandrasekar A
      • Board TN
      Bone allograft in the UK : perceptions and realities.
      ]. Based on the reported numbers of HIV and HCV transmissions from allograft bone in relation to large numbers of transplants done worldwide every year, the screening procedures and secondary serologic testing seem to be very effective, making the risk of viral transmission negligible [
      • Kinaci A
      • Neuhaus V
      • Ring DC
      Trends in bone graft use in the United States.
      ].

      Safety of DBM

      Donors of bone used for DBM are screened and tested like other allograft donors, and processing procedures and demand of sterility is regulated [
      • Taylor DW
      • Bohm KC
      • Taylor JE
      • Gross AE
      Use of fresh osteochondral allograft in repair of distal femur after trauma.
      ]. In relation to harvesting, all grafts are microbiological tested and, if positive, the graft is declined [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ]. Due to the high risk of secondary contamination during harvesting and transport of the allograft, bone banks utilise preventive procedures before final processing that include debridement, antibiotic solutions, alcohol baths, and intensive washing. After pulverisation, the next step in making DBM is demineralisation in an acid solution, after which most viruses are inactivated [
      • Taylor DW
      • Bohm KC
      • Taylor JE
      • Gross AE
      Use of fresh osteochondral allograft in repair of distal femur after trauma.
      ]. Further sterilisation procedures include different methods like dry heat sterilisation, ethylene oxide, irradiation, gas, or ultraviolet light according to the manufacturer's choice and regulatory demands. The FDA demand a sterility assurance level of 10−6 in all DBM products, meaning that no more than one unit out of one million would fail a sterility test [
      • Taylor DW
      • Bohm KC
      • Taylor JE
      • Gross AE
      Use of fresh osteochondral allograft in repair of distal femur after trauma.
      ]. Like in allograft bone, no steps in DBM processing can eliminate prions, which can only be limited through careful donor screening. In the literature there are no reports of infectious disease transmission from any commercial DBM products [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ].
      Dinopoulos and Giannoudis argue that the greatest theoretical risk from using a DBM product is from excipients of preparations [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ]. An animal study testing the Grafton DBM product in mice discovered a dramatic and lethal effect when used in doses eight times higher than recommended in humans. The glycerol used as a carrier was suspected to be the causative agent [
      • Bostrom MPG
      • Yang X
      • Kennan M
      • Sandhu H
      • Dicarlo E
      • Lane JM
      An Unexpected Outcome During Testing of Commercially Available Demineralized Bone Graft Materials How Safe Are the Nonallograft Components ?.
      ]. Small amounts of residual antibiotics that have been used during the disinfection processes may also still be present in DBM, with the potential to produce an allergic reaction in the recipient [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ]. As DBM is used locally and in small doses systemic reactions are very unlikely. The immunological reactions from DBM are greatly reduced by decellularization during processing, but theoretically a potential risk is present from the remaining specific bone proteins. However, there is no evidence from either preclinical testing or clinical reports that immunological responses are responsible for graft rejection [
      • Dinopoulos HTH
      • Giannoudis P.
      Safety and efficacy of use of demineralised bone matrix in orthopaedic and trauma surgery.
      ].
      For both allograft bone and DBM, the safety depends on a coherent chain of screening and processing, but the recipient remains at risk if this chain is broken. Unfortunately, there are several examples of the allograft industry having broken the chain of safety, with serious regulatory violations during screening, procurement, processing, and sterilisation [
      • McAllister DR
      • Joyce MJ
      • Mann BJ
      • Vangsness CT
      Allograft update: the current status of tissue regulation, procurement, processing, and sterilization.
      ].

      Cost

      It has not been possible to find any cost-effectiveness studies that compare bank allograft bone with DBM. An economic comparison is thus limited to presenting price examples of allograft and DBM.

      Cost of allograft bone

      The price of allograft bone varies depending on whether it is bone from a bone bank, where the price is conditional of the costs of establishing and operating the bone bank, or it is bone from external suppliers. From the literature, the prices of femoral heads range from US $435 to US $1818 from a hospital-run bone bank, up to US $2793 per commercially purchased allografts. The large variation in price may be contingent on the fact that papers represent a period of time, from the beginning of 2000 up to 2014 [
      • Benninger E
      • Zingg PO
      • Kamath AF
      • Dora C
      Cost analysis of fresh-frozen femoral head allografts : Is it worthwhile to run a bone bank?.
      ,
      • Barrington GV.
      Canadian Council for Donation and Transplantation (CCDT).
      ,
      • Shen WY
      • Leung HB
      • Fok MWM
      • Chow LCY
      • Yen C
      Cost comparison of femoral head banking versus bone substitutes.
      ,
      • Roberts TT
      • Rosenbaum AJ.
      Bone grafts, bone substitutes and orthobiologics The bridge between basic science and clinical advancements in fracture healing.
      ]. Brown et al. estimated that a femoral head can provide approximately 50 cm3 of morselised allograft bone [
      • Brown DA
      • Mallory GW
      • Higgins DM
      • Abdulaziz M
      • Huddleston PM
      • Nassr A
      • et al.
      A cost-effective method for femoral head allograft procurement for spinal arthrodesis: an alternative to commercially available allograft.
      ]. Based on the above reported cost per femoral head and expected volume of morselised graft for use, the calculated price may then vary from US $8.7 up to US $55.86 per cm3. The cost per volume is dependent on the variable head size. Roberts calculated the cost of cancellous chips to be US $13 per cm3 [
      • Roberts TT
      • Rosenbaum AJ.
      Bone grafts, bone substitutes and orthobiologics The bridge between basic science and clinical advancements in fracture healing.
      ].

      Cost of DBM

      A report posted in 2008 compared commercial DBM products from 17 different manufacturers, with prices varying from US $109 up to US $1720 per cm3 [

      Mendenhall and Associates Inc. Bone grafts and bone substitutes. 2008.

      ]. Roberts paper from 2012 reported the cost of DBM from US $726 up to US $1225 per cm3 [
      • Roberts TT
      • Rosenbaum AJ.
      Bone grafts, bone substitutes and orthobiologics The bridge between basic science and clinical advancements in fracture healing.
      ].

      Patient acceptance

      The surgeon's choice of bone substitute will, in particular, be influenced by the volume required, evidence in relation to the efficacy and the economy, but how about the patient's opinion? In relation to orthopaedic trauma surgery this question cannot be answered from the existing literature and it is necessary to consult the literature pertaining to dental patients.

      Patient acceptance of allograft

      A survey study by Bucchi et. al asked 330 patients from five different countries about their opinion regarding the use and origin of bone grafts used in dental surgery [

      Bucchi C, Fabbro M, Arias A, Mendes JM, Ordonneau M, Orti V. Multicenter study of patients ’ preferences and concerns regarding the origin of bone grafts utilized in dentistry. Patient Prefer Adherence 2019:179–85.

      ]. One fifth would never accept allograft and one fifth would only accept it as last resort. The main reasons to reject allograft were ethical/moral concerns and the secondary fear of disease transmissions. In another study by one of the same authors, of 100 dental patients included, 41% would never accept allograft or only do so as a last resort, 17% would refuse because they felt it wrong to use bone material from other human being, and 15% would refuse allograft due to fear of disease transmission from the graft [
      • Fernández RF
      • Bucchi C
      • Navarro P
      • Beltrán V
      • Borie E
      Bone grafts utilized in dentistry: an analysis of patients’ preferences.
      ]. A study by Güngörmüs et al. evaluated a similar patient population regarding grafts used in maxillofacial surgery and found that 46.8% rejected allografts. Seventy percent of patients cited the reason was fear of infection, 12.6% because of a foreign product, and 3.2% for religious reasons [
      • Güngörmüş Z
      • Güngörmüş M.
      Effect of religious belief on selecting of graft material used in oral and maxillofacial surgery.
      ]. Similarly, 34.9% would reject a synthetic graft.

      Patient acceptance of DBM

      No studies were found with specific focus on DBM. Although DBM origins from allograft bone, then perhaps from a patient's perspective DBM is more likely to be categorized along with synthetic bone products. If so, then Bucchi et. al it revealed that 1.8% would never accept the use of synthetic bone materials (not specified), and 4.5% would only accept such as a last resort [

      Bucchi C, Fabbro M, Arias A, Mendes JM, Ordonneau M, Orti V. Multicenter study of patients ’ preferences and concerns regarding the origin of bone grafts utilized in dentistry. Patient Prefer Adherence 2019:179–85.

      ]. From the study by Güngörmüs et al. 34.9% would reject a synthetic graft [
      • Güngörmüş Z
      • Güngörmüş M.
      Effect of religious belief on selecting of graft material used in oral and maxillofacial surgery.
      ].

      Conclusion

      In trauma surgery there is a need for alternatives to autograft bone; this study compared allograft with DBM regarding efficacy, clinical evidence, safety, cost, and patient acceptance. The results are summarised in Table 3. A literature search revealed that papers regarding the specific use of allograft and DBM in trauma surgery are sparse, and most represent low-level evidence. In line with the conclusions from two systematic review papers it is difficult to point out where DBM is useful in trauma surgery [
      • van der Stok J
      • Hartholt KA
      Schoenmakers, DAL;Arts J.
      The available evidence on demineralised bone matrix in trauma and orthopaedic surgery.
      ,
      • Drosos GI
      • Touzopoulos P
      • Ververidis A
      • Tilkeridis K
      • Kazakos K
      Use of demineralized bone matrix in the extremities.
      ]. DBM is regarded as safer, and it has also been concluded that the risk of disease transfer from bone bank allograft to recipient is negligible. A cost comparison is in favour of allograft with the price per cm3 found to be from two to 30 times higher when using DBM. While an unambiguous conclusion on patient acceptance in orthopaedics is not possible, dental patients have a high aversion to allograft.
      Table 3Comparison of allograft and DBM in trauma surgery.
      AllograftDBMFavors
      EfficacyOsteoconduction++Both
      Osteoinduction+++DBM
      Mechanical support++-Allograft
      Clinical evidence+/--Allograft
      Safety++++DBM
      Low cost+++Allograft
      Patient acceptance+++DBM
      It is not possible to definitively conclude whether it makes a difference if allograft or DBM is used in trauma surgery. It is ultimately the surgeon's choice. Nonetheless, this article may be useful in providing considerations before a decision is made.

      Declaration of Interest Statement

      The author declare that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      The author of this manuscript express thanks to the Osteosynthesis and Trauma Care Foundation for the sponsorship of having the publication of this Supplement in Injury.

      Funding

      None.

      Appendix. Supplementary materials

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