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Bone scaffolds: The role of mechanical stability and instrumentation
Injury, Int. J. Care Injured (2005) 36S, S38—S44
www.elsevier.com/locate/injury
Bone scaffolds: The role of mechanical stability and instrumentation George C. Babis *, Panayotis N. Soucacos 1st Department of Orthopaedic Surgery, 2 Nikis Street, 145 61 Kifissia, KAT Accident Hospital and Attikon University Hospital, University of Athens Medical School, Greece
KEYWORDS Mechanical stability; Scaffolds; Osteoconduction; Regeneration
Summary Osteoconductive bone scaffolds are increasingly used today for regeneration of bone defects. Research is mainly focused on the scaffold material, its macro and micro architecture and mechanical properties. The mechanical environment and the optimal instrumentation, used to protect and enhance bone regeneration, are multifactorial issues and have not yet received the appropriate attention by researchers in the field. # 2005 Elsevier Ltd. All rights reserved.
Introduction Bone stock loss may occur primarily due to trauma, but also due to genetic disorders, infection, tumors and other conditions. Since bone is a living tissue, with constant remodelling sustained by the regulated action of osteoclasts and osteoblasts, its loss should be viewed not only from the loss of its structural integrity but also from the injury to bone circulation and the absence of living cells. Mechanical stability and the biological potential of bone and the surrounding soft tissues are the two crucial prerequisites for bone regeneration and fracture healing.27 Both, clinical practice and basic science, have shown that these parameters are so uniquely interlaced and in such a way that, a change in one of them directly affects the other and the final outcome. Many in vivo studies demonstrate the important role of mechano-sensitivity of bone * Corresponding author. Tel.: +30 210 6280209 E-mail address: [email protected] (G.C. Babis).
tissue and the interaction between biomaterials and bone.18,29 The purpose of this review is to highlight the role of mechanical stability provided by various modes of instrumentation in bone fracture healing and regeneration, to show how it affects the biology of bone and consequently of bone scaffolds that are used for replacement of bone lost through injury or disease.
The role of mechanical stability in bone union The role of mechanical stability in fracture fixation has evolved from the period of inadequate implant fixation, to the era of ORIF (open reduction and internal fixation) as popularized by the AO, and finally to the concept of biologic fixation.27 Unstable fixation often leads to catastrophic results such as delayed union, non-union or loss of reduction. Absolutely stable anatomic fixation usually results in primary bone union achieved by direct haversian
0020–1383/$ — see front matter # 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2005.10.009
Bone scaffolds: The role of mechanical stability and instrumentation remodelling.28 However, even these techniques were not immune of serious complications that included delayed union, non-union, refractures after device removal, and infection. Today the preferred method of fracture fixation relies on preservation of blood supply and relative stability that leads to bone union through secondary callus formation. The later has provided more consistent and reliable results.27
The role of mechanical strain Strain is a mechanical term that expresses the relative motion between two rigid bodies. Strain is defined as the relative change in a gap divided by the initial gap that separates them (strain = dl/l). This term was used initially by Perren22 in his effort to associate bone fracture healing, the initial fracture gap and the rigidity of fixation. This theory is based on his observation that ‘‘tissue cannot be produced under strain conditions which exceed the elongation at time of tissue rupture’’. Whereas granulation tissue ruptures at a strain of approximately 100%, lamellar bone can only sustain a strain of only 2%. Therefore, the type of healing that occurs at the fracture site is governed by the fracture gap and the strain. Interfragmentary strain is inversely proportional to the fracture gap size. Thus, by increasing the gap, the strain is lowered. Although it would seem rationale to increase the fracture gap in order to decrease strain, it has been shown that fracture gap size had more influence on the healing process than interfragmentary strain, and that increasing gap size resulted in poorer mechanical and histological qualities.1 In the case of absolute stability at the fracture site with strain less than 2% (rigid fixation) primary bone healing occurs, provided that the bone ends are in intimate contact. Rigid fixation is afforded by compression plating or by neutralization plates after interfragmentary screw compression. In situations with relative interfragmentary stability with strain between 2 and 10%, secondary bone healing occurs. Relative stability can be provided in an increasing degree by splints, casts, intramedullary nails, external fixators and locked plates. Non-union may occur when interfragmentary strain exceeds 10%.
Allograft bone union and incorporation Cortical allograft bone incorporation in humans was documented by Enneking and Mindell.9 The authors evaluated histologically 16 retrieved massive human allografts performed after tumour resections. They
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found that host bone to allograft union is achieved by intramembranous bone formation from reconstituted periosteum. Cancellous allograft incorporation is much faster than cortical bone primarily due to faster revascularization.9 The inner zone of the allograft remained necrotic and is essentially acellular.
Mechanical environment and remodelling of bone scaffolds It is well known that living bone adapts to mechanical load according to Wolff’s law35; strain induces bone and lack of strain leads to bone resorption. Although the exact mechanism of bone remodelling is not known, it has been postulated that strain induces changes in the anabolic activity of osteocytes.19 Strain may directly affect osteocytes or indirectly affect osteoblasts by changes in the pericellular hydrostatic pressure.25 Furthermore, intermittent hydrostatic pressures have been shown to cause anabolic and catabolic effects on osteoblasts in vitro.25 Consequently, vascularized bone grafts are expected to adapt to mechanical strain. Surprisingly there is also evidence of bulk allograft remodelling, a bone with no living cells.31 These authors found in biopsy specimens that only a few millimetres of the allograft were replaced by living bone, the rest being necrotic. Bauer and Muschler2 speculated that ‘‘hydrostatic pressures or streaming potentials of ions associated with strain are transmitted to graft surface where these signals are transduced into cytokine signals by osteoblasts, osteocytes, or other surface lining cells that in turn influence activation of bone remodelling units’’. Cancellous bone scaffolds are remodelled by new bone formation faster. It is intriguing that some acellular scaffolds may be also remodelled. In an animal model, an injectable calcium phosphate cement (Norian Skeletal Repair System, SRS1, Cupertino, CA), was replaced and remodelled by haversian host bone systems when it was subjected to compressive loads.11 This suggests that mechanical loads can also influence the rate of remodelling of skeletal substitute materials. Norian SRS1 has a high extent of microporosity and would be capable of transmitting changes in hydrostatic pressures that might influence bone remodelling in a manner similar to that of conventional bone graft. Bauer and Muschler2 suggested that ‘‘for a synthetic material to respond to Wolff’s law,35 it must meet several requirements: (1) it must be osteoconductive so that it can become physically and mechanically incorporated with the host such that mechanical loads are transmitted through the graft site; (2) it
S40 must have mechanical properties that prevent mechanical failure (fracture, deformation, or particulate wear) under the loads experienced in vivo; and (3) it must be composed of a material that permits or facilitates osteoclastic resorption’’. Porosity is essential because it allows transmission of changes in hydrodynamic pressure or streaming potentials throughout the bulk of the material. The authors concluded that under these circumstances, it seems likely that at least some acellular skeletal substitute materials may undergo remodelling in response to load.
Mechanical properties of bone scaffolds The mechanical properties as well as the rate and extend of remodelling vary greatly among bone scaffold materials. These properties are influenced by many factors, including the nature of the graft itself, the quality of the host site and the local mechanical environment (strain). The mechanical properties of the scaffold depends on the material from which is made (i.e. allograft trabecular bone, cortical alloraft strut, xenograft trabecular bone, tricalcium phosphate ceramics (TCP), hydroxyapatite (HA), polylactic acid (PLA), polyglycolic acid (PGA), copolymers of PLA and PGA, bioactive glasses or bio-composites). Graft macro and micro architecture, and the extent and type of porosity are other factors that directly affect the mechanical strength of various scaffolds. Most importantly, bone graft mechanics eventually change with the progress of the incorporation remodelling process. Fresh frozen cortical strut allografts have initially mechanical properties similar to living cortical bone. However, these scaffolds lack the ability of a repair process of micro-fracture crack propagation and they can eventually fail. In addition, remodelling by vascular invasion and creeping substitution by the host bone is very slow and may take up several years with a remaining greater proportion of necrotic graft bone to viable host bone.4,7 Finally, the healing of bone-graft junction may respond to the mechanical environment. Autogenous or allograft cancellous bone grafts, and demineralized bone matrix putty have no real biomechanical properties to support and sustain physiologic loads; they often are supported by internal or external fixation when used to reconstruct non-contained defects. When these scaffolds are used to support contained defects or the subchondral bone in intra-articular fractures they should be placed under pressure (impaction grafting) and
G.C. Babis, P.N. Soucacos protected by the use of internal fixation devices or implants.14 The mechanical properties of calcium phosphate scaffolds are not suited to withstand torsional and tensile forces imposed on the skeleton; they are more brittle and have less tensile strength than bone.32 Their clinical use is limited to non-weight bearing sites and often requires stress shielding support by means, such as plates or screws. Once the scaffold has incorporated with surrounding hard tissue, its mechanical strength approaches that of cancellous bone.32 Ceramic scaffolds are typically used to fill cystic defects, repair fractures of the tibial plateau, and extend autogenous bone grafts.17 Calcium phosphate cements have a fragility profile similar to traditional calcium phosphates. They have compressive strength in a range of 10— 100 mPa, a value, which is much higher than their tensile strength (1—10 mPa).3,32 This necessitates their use in either low or non-load bearing applications or in combination with metal implants. Norian SRS, a tricalcium phosphate cement, hardens approximately 12 h after injection, and its compressive strength is approximately 55 MPa. This is roughly 4—10 times greater than the average compressive strength of cancellous bone. The mechanical properties and the minimum degradation of glass-ceramic cylinders, found in a femoral bone diaphyseal critical defect study in rabbits, suggests that this substitute may be preferable in clinical situations of intense mechanical requirements or load bearing.13 Whether the adjacent host bone bed is osteoporotic or not, plays a significant role in local biomechanics. In addition, local biomechanics differ considerably if the scaffold material is placed in a relatively non-weight bearing area (i.e. to fill a bone cyst), in a contained or not bone defect, or it is used to reconstruct a segmental diaphyseal defect. The task of developing a device for bone replacement carries with it the additional requirement of high strength. Consequently, the scaffold should be designed to exceed the strength of the natural bone it replaces. 3D porous polymer scaffolds have demonstrated compressive mechanical strength and modulus within the normal ranges of trabecular bone properties. Pore sizes in the range of 150— 500 mm are optimal for interface activity, bone ingrowth, and implant resorption.32,33 Current research is directed toward understanding the change in strength that occurs as the scaffold is broken down over time in the body and is built up by ingrowth of new bone tissue.13 The purpose is to ensure that adequate strength is maintained throughout the period of bone remodelling.
Bone scaffolds: The role of mechanical stability and instrumentation
The role of internal fixation devices The influence of hardware fixation in conjunction with bone graft materials is a very complex issue, and there is little written in the literature. Hardware is very often necessary to provide sufficient stability to allow for graft incorporation. The exact extent to which the bone graft must be shielded from load by the hardware is virtually unknown to date. Internal fixation devices include, conventional plates and screws, locked compression plates (LCP), intramedullary nails, and external fixators. In joint reconstruction bone scaffolds can be protected by anti-protrusio rings, cups and cages, by cerclage wires or by distal fixation femoral systems in the case of proximal femoral bone loss and the need for its reconstruction. In general, plate—screw—bone constructs can act as load-sharing or load-bearing devices depending on fracture reduction and fragment interference. Neutralization plates function as load-sharing devices.5,12 These plates neutralize the effect of bending, rotational, and axial forces on the fracture site. In light of the fact that bone can withstand compression and metal can withstand tension, the plates should be placed in the tensile part of the equilibrium. The weakest link in the plate—screw— bone construct, both in neutralization and in dynamic compression plates, is the shear interface between the screw and the bone. In osteoporotic bone, improvements in plate fixation are directed to reduce the stress at the screw—bone interface by increasing the contact area between the screw and the bone. This can be done by the use of polymethyl methacrylate [PMMA] in the screw holes or by using HA coated screws. Another way to achieve this goal is by changing the stress at the screw—bone interface from shear stress (pullout) to compressive stress (locking plates).8 Conventional plates and screws may be (a) inadequate in achieving fixation in osteopenic or pathologic bone; (b) can lead to necrosis under the plate witch predisposes to infection; (c) may result in stress shielding which weakens the bone and increases the potential for refracture after device removal; and (d) create an environment where lack of stability may result to delayed union or non-union. Therefore, compression plating have limited use today, but may continue to be the method of choice for periarticular fractures, forearm fractures without bone loss where anatomic reduction is necessary to preserve motion, and certain types of non-unions where increasing stability can lead to union. In the presence of bone defects, where bone scaffolds may be used to reconstruct bone stock,
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there is increased need for a stable construct to effectively shield the graft material from excessive loading. Under these circumstances, plates are functioning as load-bearing devices. At the screw—bone interface locking plates convert shear stress to compressive stress and therefore fixation is improved because bone has much higher resistance to compressive stress than to shear stress. The difference in locked plates is that the strength of fixation equals the sum of all screw—bone interfaces rather than that of a single screw’s axial stiffness or pullout resistance as seen in unlocked plates.6 Furthermore locked plates act as ‘‘internal external fixators’’ (extremely rigid fixators) because of their very close proximity to the bone and fracture site. Consequently, locked plates may be the implant of choice in situations where bone scaffolds are used to regenerate bone stock loss.20 Buttress plates are load-bearing devices that act to counter shear forces at a fracture site by converting them to compressive axial forces. These plates are placed at the apex of the fracture. This technique is used to treat many intra-articular fractures as the tibial plateau fractures (Fig. 1a and b). Calcium phosphate has been used in depressed intra-articular tibial plateau fractures and compared favourably to cancellous bone grafts in biomechanical studies. In a study of 26 patients undergoing open reduction and internal fixation of displaced tibial plateau fractures, calcium phosphate was found to produce good outcomes. Because of the high mechanical strength of the cement, the authors allowed early weight bearing after a mean postoperative period of 4.5 weeks, with a range from 1 to 6 weeks. Despite early weight bearing, only 2 patients in this series suffered from a partial loss of reduction. Intramedullary nails are an example of internal splint fixation.24 The nail splints and bestows stability in a mode analogous to a tube within a tube.27 This type of fixation has unique biological and mechanical advantages over the plates and screws. The nails are placed near the neutral axis of bending of the bone, therefore being stronger than plates and can withstand loading for longer periods than plates until failure. Clinical results of closed intramedullary nailing have been proved superior to all other types of fixation in diaphyseal fractures and have been established as the method of choice.34 Unfortunately nailing, especially when intramedullary reaming is utilised, produces damage to the intramedullary blood supply of bone.23,26 Despite this theoretical disadvantage, closed techniques of reaming and nailing preserves the extraosseous and periosteal blood supply to bone and provide uneventful healing in the majority of cases.15
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Figure 1 (a) Anteroposterior knee X-ray showing a Schatzker type II tibial plateau fracture where Xenograft scaffold was used to support the depressed intra-articular surface and a buttress plate to counter shear forces at a fracture site by converting them to compressive axial forces. (b) Union of the fracture 4 months later.
In the case of segmental defects, although nailing provides an excellent biomechanical environment, the open technique needed for preparation of the host bone bed and insertion of bone scaffold devitalizes the blood supply in conjunction with the medullary blood supply damage caused by the
G.C. Babis, P.N. Soucacos reaming and nailing. In an experimental animal study of large (4—7 cm) diaphyseal defects, Meining20 found that intramedullary nailing used to shield a polylactide membrane scaffold caused avasularity in bone ends leading to poor bone regeneration. When the author used two locking plates applied orthogonally the membranes promoted spontaneous bone regeneration across the defect and clinical union.20 External fixators provide a relatively unstable fixation and it is used in various forms to treat open type III Gustilo fractures or infected non-unions. However, the stiffness of the construct depends on various factors such as the number and diameter of pins or half-pins, the distance of the pins from the fracture, the distance of the rod from the bone, etc. Circular external fixators as the Ilizarov frame have lower rigidity, especially in compression, and lower lateralmedial bending rigidity compared to HoffmannVidal half-pin frame. Nevertheless, lower rigidity and consequent micro-movement may be advantageous in providing axial loading to the regenerate bone.16 Cages in conjunction with autograft, allograft, and other scaffolds have been used extensively both in animal models and clinically in human spines to help achieve spinal fusion. Although only few of the experimental data are standardized through valid double blind controlled studies, there is general agreement that cages provide a biomechanical environment for scaffold materials to be incorporated and remodelled. In distal radial fractures the use of calcium phosphate combined with K-wire fixation was more stable than fixation with K-wires alone, but both were significantly less stable than external fixation that was augmented with calcium phosphate.14 Whereas internal or external fixation provides stress shielding for bone scaffolds, there are circumstances that the later enhance the stability of bone-instrumentation construct. In hip fractures calcium phosphate has been studied as adjunctive fixation in both femoral neck and intertrochanteric hip fractures especially in cases with extensive osteoporosis. In one prospective clinical study, patients with displaced femoral neck fractures were randomised in two groups. One group underwent closed reduction and fixation with 2 cannulated screws with augmentation using Norian SRS1 around the screws; in the other group only screws were used. Radiosteriometric analysis showed significantly better early stability of the fracture site at 1 and 6 weeks. Greater stiffness in specimens fixed with cannulated screws augmented with calcium phosphate was found in a biomechanical investigation compared to specimen fixed with screws alone. In a biomechanical investigation of simulated
Bone scaffolds: The role of mechanical stability and instrumentation
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There has been no mechanical failure so far, however longer follow up is needed for safe conclusions.
Biodegradable implants
Figure 2 Anteroposterior pelvis X-ray showing incorporation of the demineralized bone scaffold material 4 months after acetabular revision in the left hip.
unstable intertrochanteric hip fractures, specimens fixed with a sliding hip screw augmented with calcium phosphate had greater stiffness, stability, strength, and less shortening at the fracture site compared to those fixed with a sliding hip screw alone. Impaction grafting is an established method for bone reconstruction of severe bone loss both in the acetabulum and proximal femur at the time of revision arthroplasty. Originally described by Sloof et al.,30 for use in the acetabulum and later adapted for use in the femur, impaction grafting involves cementing a femoral component into compressed bone graft, usually morselized allograft.10 Instrumentation and biomechanics play a significant role in this application. The femoral stem, being polished and having a tapered shape, converts shear loads into radial compression forces (hoop stresses) while migrating distally. Graft remodelling has been documented in biopsy specimens taken during cement removal in some cases.21 In our department there is considerable experience with cotyloplasty, a method to restore the acetabular medial wall in CDH cases. The moselized allograft, placed in a well-vascularized bone bed and protected by the use of cement, regenerated consistently the inner wall of the acetabulum. This technique is currently extended also to revision cases with large contained defects. From 2001, 29 acetabular revisions with extended contained bone stock deficiencies were treated by meticulous preparation of the host bone bed, large quantities of allograft demiteralized bone matrix pressurized by reversed reaming and protected by the use of cementless HA coated antiprotrusio cups with a hook and external fins with screws. In all cases bone scaffolds were incorporated as seen in plain X-rays from the disappearance of scaffold-host reversed cement lines (Fig. 2).
Biodegradable implants can be fabricated in a way that at the same time play the roles of biomimetic scaffold while providing adequate stability and release bone morphogenetic proteins in a controlled manner so that the proper amounts are released over the right time period at the site of interest. The implant will enable healing by stabilizing the gap and offering a welcome environment for the body’s own bone cells. The implant will break down over time, as the patient’s own bone cells move in and produce replacement bone.
Conclusions In applications such as bone and cartilage tissue engineering, scaffold materials are often necessary to provide a platform on which cells can attach, grow, and proliferate. For load-bearing applications, these scaffolds must possess sufficient initial mechanical properties equivalent to healthy bone to prevent immediate failure upon implantation. In addition, scaffolds must be biodegradable, microporous, nano-structured biomimetic materials that are capable of transmitting changes in hydrostatic pressures that might influence bone remodelling in a manner similar to that of conventional bone grafts. Up to date bone scaffolds must be protected by the use of specific metallic implants, which should function until a prolonged period of time as load bearing devices. With the progress of bone scaffold incorporation and remodelling assuming mechanical properties, these implants will eventually become load shearing and therefore will be protected from implant failure.
References 1. Augat P, Margevicius K, Simon J, et al. Local tissue properties in bone healing: influence of size and stability of the osteotomy gap. J Orthop Res 1998;16:475—81. 2. Bauer TW, Muschler GF. Bone graft materials: an overview of the basic science. Clin Orthop 2000;371:10—27. 3. Bohner M. Calcium orthophosphates in medicine: from ceramics to calcium phosphate cements. Injury 2000;31(Suppl. 4): SD37—47. 4. Burchardt H. Biology of cortical bone graft incorporation. In: Friedlaender GE, Mankin HJ, Sell KW, editors. Osteochondral allografts.. New York, NY: Little, Brown, 1981. 5. Burstein AHWT. Fundamentals of orthopaedic biomechanics. Baltimore, MD: Williams and Wilkins, 1994.
S44 6. Cordey J, Borgeaud M, Perren SM. Force transfer between the plate and the bone: relative importance of the bending stiffness of the screws friction between plate and bone. Injury 2000;31(Suppl. 3):C21—8. 7. Day SM, Ostrum RF, Chao EYS, et al. Bone injury, regeneration, and repair. In: Orthopaedic basic science. Rosemont Il: American Academy of Orthopaedic Surgeons, 2000. 8. Egol KA, Kubiak EN, Fulkerson E, et al. Biomechanics of locked plates and screws. J Orthop Trauma 2004;18(8): 488—93. 9. Enneking WF, Mindell ER. Observations on massive retrieved human allografts. J Bone Joint Surg 1991;73A:1123—42. 10. Fowler JL, Gie GA, Lee AJ, Ling RS. Experience with the Exeter total hip replacement since 1970. Orthop Clin North Am 1988;19:477—89. 11. Frankenburg EP, Goldstein SA, Bauer TW, et al. Biomechanical and histological evaluation of a calcium phosphate cement. J Bone Joint Surg 1998;80A:1112—24. 12. Gautier E, Perren SM, Ganz R. Principle of internal fixation. Curr Orthop 1992;6:220—32. 13. Gil-Albarova J, Salinas AJ, Bueno-Lozano AL, et al. The in vivo behaviour of a sol—gel glass and a glass-ceramic during critical diaphyseal bone defects healing. Biomaterials 2005;26(21):4374—82. 14. Higgins TF, Dodds SD, Wolfe SW. A biomechanical analysis of fixation of intra-articular distal radial fractures with calciumphosphate bone cement. J Bone Joint Surg Am 2002;84: 1579—86. 15. Karachalios T, Babis GC, Tsarouchas J, et al. Interlocking tibial nailing without exposure to radiation. Clinical efficacy and an assessment of the ease and safety of distal locking with the use of an improved targeting system. Injury 2000;31(6):451—9. 16. Kenwright J, Goodship AE. Controlled mechanical stimulation in the treatment of tibial fractures. Clin Orthop 1989;24: 36—47. 17. Khan SN, Tomin E, Lane JM. Clinical applications of bone graft substitutes. Orthop Clin North Am 2000;31(3):389—98. 18. Lacroix D, Prendergast PJ. A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J Biomech 2002;35:1163—71. 19. Lanyon LE. Control of bone architecture by functional load bearing. J Bone Miner Res 1992;7:369—75.
G.C. Babis, P.N. Soucacos 20. Meining RP. Polylactide membranes in the treatment of segmental diaphyseal defects: animal model experiments in rabbit radius, sheep tibia, Yucatan minipig radius, and goat tibia. Injury 2002;33(Suppl. 2):S-B58—65. 21. Nelissen RGHH, Bauer TW, Weidenhielm LRA, et al. Revision hip arthroplasty with the use of cement and impaction grafting. J Bone Joint Surg 1995;77A:412—22. 22. Perren SM. Physical and biological aspects of fracture healing with special reference to internal fixation. Clin Orthop 1979;138:175—96. 23. Perren SM. The concept of biological plating using the limited contact-dynamic compression plate (LC-DCP). Scientific background, design and application. Injury 1991;22(Suppl. 1):S5. 24. Perren SM. Some clinical relevant properties of the intramedullary nail. Injury 1999;30(Suppl. 3):S-C2—4. 25. Reich KM, Gay CV, Frangos JA. Fluid shear stress as a mediator of osteoblast cyclic adenosine monophosphate production. J Cell Physiol 1990;143:100—4. 26. Rhinelander FW. Effects of medullary nailing on the normal blood supply of diaphyseal cortex. In: A.A.O.S. Instructional course lectures. Mosby: St. Louis, 1973. p. 161—87. 27. Schatzker J, Tile M. The rationale of operative fracture care, 2nd ed., New York: Springer-Verlag, Berlin, Heidelberg, 1996. 28. Schenk R, Willenegger H. Zum histologischen bild der sogenannten prima ¨rheilung der knochenkompakta nach experimentellen osteotomen am hund. Experientia 1963;19:593. 29. Sikavitsas VI, Temenoff JS, Mikos AG. Biomaterials and bone mechanotransduction. Biomaterials 2001;22(19):2581—93. 30. Sloof TJ, Huiskes R, van Horn J, Lemmens AJ. Bone grafting in total hip replacement for acetabular protrusion. Acta Orthop Scand 1984;55:593—6. 31. Trancik TM, Stulberg BN, Wilde AH, Feiglin DH. Allograft reconstruction of the acetabulum during revision total hip arthroplasty. J Bone Joint Surg 1986;68A:527—33. 32. Truumees E, Herkowitz HN. Alternatives to autologous bone harvest in spine surgery. Univ Pen Orthop J 1999;12:77—88. 33. Vaccaro A. The role of the osteoconductive scaffold in synthetic bone graft. Orthopedics 2002;25:s577—8. 34. Winquist RA, Hansen ST, Clawson DK. Closed intramedullary nailing of femoral fractures. J Bone Joint Surg 1984;66A:529— 39. 35. Wolff J. Das gesetz der transformation der knochen. Berlin: Verlag von Augsut Hirschwald; 1892.
www.elsevier.com/locate/injury
Bone scaffolds: The role of mechanical stability and instrumentation George C. Babis *, Panayotis N. Soucacos 1st Department of Orthopaedic Surgery, 2 Nikis Street, 145 61 Kifissia, KAT Accident Hospital and Attikon University Hospital, University of Athens Medical School, Greece
KEYWORDS Mechanical stability; Scaffolds; Osteoconduction; Regeneration
Summary Osteoconductive bone scaffolds are increasingly used today for regeneration of bone defects. Research is mainly focused on the scaffold material, its macro and micro architecture and mechanical properties. The mechanical environment and the optimal instrumentation, used to protect and enhance bone regeneration, are multifactorial issues and have not yet received the appropriate attention by researchers in the field. # 2005 Elsevier Ltd. All rights reserved.
Introduction Bone stock loss may occur primarily due to trauma, but also due to genetic disorders, infection, tumors and other conditions. Since bone is a living tissue, with constant remodelling sustained by the regulated action of osteoclasts and osteoblasts, its loss should be viewed not only from the loss of its structural integrity but also from the injury to bone circulation and the absence of living cells. Mechanical stability and the biological potential of bone and the surrounding soft tissues are the two crucial prerequisites for bone regeneration and fracture healing.27 Both, clinical practice and basic science, have shown that these parameters are so uniquely interlaced and in such a way that, a change in one of them directly affects the other and the final outcome. Many in vivo studies demonstrate the important role of mechano-sensitivity of bone * Corresponding author. Tel.: +30 210 6280209 E-mail address: [email protected] (G.C. Babis).
tissue and the interaction between biomaterials and bone.18,29 The purpose of this review is to highlight the role of mechanical stability provided by various modes of instrumentation in bone fracture healing and regeneration, to show how it affects the biology of bone and consequently of bone scaffolds that are used for replacement of bone lost through injury or disease.
The role of mechanical stability in bone union The role of mechanical stability in fracture fixation has evolved from the period of inadequate implant fixation, to the era of ORIF (open reduction and internal fixation) as popularized by the AO, and finally to the concept of biologic fixation.27 Unstable fixation often leads to catastrophic results such as delayed union, non-union or loss of reduction. Absolutely stable anatomic fixation usually results in primary bone union achieved by direct haversian
0020–1383/$ — see front matter # 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2005.10.009
Bone scaffolds: The role of mechanical stability and instrumentation remodelling.28 However, even these techniques were not immune of serious complications that included delayed union, non-union, refractures after device removal, and infection. Today the preferred method of fracture fixation relies on preservation of blood supply and relative stability that leads to bone union through secondary callus formation. The later has provided more consistent and reliable results.27
The role of mechanical strain Strain is a mechanical term that expresses the relative motion between two rigid bodies. Strain is defined as the relative change in a gap divided by the initial gap that separates them (strain = dl/l). This term was used initially by Perren22 in his effort to associate bone fracture healing, the initial fracture gap and the rigidity of fixation. This theory is based on his observation that ‘‘tissue cannot be produced under strain conditions which exceed the elongation at time of tissue rupture’’. Whereas granulation tissue ruptures at a strain of approximately 100%, lamellar bone can only sustain a strain of only 2%. Therefore, the type of healing that occurs at the fracture site is governed by the fracture gap and the strain. Interfragmentary strain is inversely proportional to the fracture gap size. Thus, by increasing the gap, the strain is lowered. Although it would seem rationale to increase the fracture gap in order to decrease strain, it has been shown that fracture gap size had more influence on the healing process than interfragmentary strain, and that increasing gap size resulted in poorer mechanical and histological qualities.1 In the case of absolute stability at the fracture site with strain less than 2% (rigid fixation) primary bone healing occurs, provided that the bone ends are in intimate contact. Rigid fixation is afforded by compression plating or by neutralization plates after interfragmentary screw compression. In situations with relative interfragmentary stability with strain between 2 and 10%, secondary bone healing occurs. Relative stability can be provided in an increasing degree by splints, casts, intramedullary nails, external fixators and locked plates. Non-union may occur when interfragmentary strain exceeds 10%.
Allograft bone union and incorporation Cortical allograft bone incorporation in humans was documented by Enneking and Mindell.9 The authors evaluated histologically 16 retrieved massive human allografts performed after tumour resections. They
S39
found that host bone to allograft union is achieved by intramembranous bone formation from reconstituted periosteum. Cancellous allograft incorporation is much faster than cortical bone primarily due to faster revascularization.9 The inner zone of the allograft remained necrotic and is essentially acellular.
Mechanical environment and remodelling of bone scaffolds It is well known that living bone adapts to mechanical load according to Wolff’s law35; strain induces bone and lack of strain leads to bone resorption. Although the exact mechanism of bone remodelling is not known, it has been postulated that strain induces changes in the anabolic activity of osteocytes.19 Strain may directly affect osteocytes or indirectly affect osteoblasts by changes in the pericellular hydrostatic pressure.25 Furthermore, intermittent hydrostatic pressures have been shown to cause anabolic and catabolic effects on osteoblasts in vitro.25 Consequently, vascularized bone grafts are expected to adapt to mechanical strain. Surprisingly there is also evidence of bulk allograft remodelling, a bone with no living cells.31 These authors found in biopsy specimens that only a few millimetres of the allograft were replaced by living bone, the rest being necrotic. Bauer and Muschler2 speculated that ‘‘hydrostatic pressures or streaming potentials of ions associated with strain are transmitted to graft surface where these signals are transduced into cytokine signals by osteoblasts, osteocytes, or other surface lining cells that in turn influence activation of bone remodelling units’’. Cancellous bone scaffolds are remodelled by new bone formation faster. It is intriguing that some acellular scaffolds may be also remodelled. In an animal model, an injectable calcium phosphate cement (Norian Skeletal Repair System, SRS1, Cupertino, CA), was replaced and remodelled by haversian host bone systems when it was subjected to compressive loads.11 This suggests that mechanical loads can also influence the rate of remodelling of skeletal substitute materials. Norian SRS1 has a high extent of microporosity and would be capable of transmitting changes in hydrostatic pressures that might influence bone remodelling in a manner similar to that of conventional bone graft. Bauer and Muschler2 suggested that ‘‘for a synthetic material to respond to Wolff’s law,35 it must meet several requirements: (1) it must be osteoconductive so that it can become physically and mechanically incorporated with the host such that mechanical loads are transmitted through the graft site; (2) it
S40 must have mechanical properties that prevent mechanical failure (fracture, deformation, or particulate wear) under the loads experienced in vivo; and (3) it must be composed of a material that permits or facilitates osteoclastic resorption’’. Porosity is essential because it allows transmission of changes in hydrodynamic pressure or streaming potentials throughout the bulk of the material. The authors concluded that under these circumstances, it seems likely that at least some acellular skeletal substitute materials may undergo remodelling in response to load.
Mechanical properties of bone scaffolds The mechanical properties as well as the rate and extend of remodelling vary greatly among bone scaffold materials. These properties are influenced by many factors, including the nature of the graft itself, the quality of the host site and the local mechanical environment (strain). The mechanical properties of the scaffold depends on the material from which is made (i.e. allograft trabecular bone, cortical alloraft strut, xenograft trabecular bone, tricalcium phosphate ceramics (TCP), hydroxyapatite (HA), polylactic acid (PLA), polyglycolic acid (PGA), copolymers of PLA and PGA, bioactive glasses or bio-composites). Graft macro and micro architecture, and the extent and type of porosity are other factors that directly affect the mechanical strength of various scaffolds. Most importantly, bone graft mechanics eventually change with the progress of the incorporation remodelling process. Fresh frozen cortical strut allografts have initially mechanical properties similar to living cortical bone. However, these scaffolds lack the ability of a repair process of micro-fracture crack propagation and they can eventually fail. In addition, remodelling by vascular invasion and creeping substitution by the host bone is very slow and may take up several years with a remaining greater proportion of necrotic graft bone to viable host bone.4,7 Finally, the healing of bone-graft junction may respond to the mechanical environment. Autogenous or allograft cancellous bone grafts, and demineralized bone matrix putty have no real biomechanical properties to support and sustain physiologic loads; they often are supported by internal or external fixation when used to reconstruct non-contained defects. When these scaffolds are used to support contained defects or the subchondral bone in intra-articular fractures they should be placed under pressure (impaction grafting) and
G.C. Babis, P.N. Soucacos protected by the use of internal fixation devices or implants.14 The mechanical properties of calcium phosphate scaffolds are not suited to withstand torsional and tensile forces imposed on the skeleton; they are more brittle and have less tensile strength than bone.32 Their clinical use is limited to non-weight bearing sites and often requires stress shielding support by means, such as plates or screws. Once the scaffold has incorporated with surrounding hard tissue, its mechanical strength approaches that of cancellous bone.32 Ceramic scaffolds are typically used to fill cystic defects, repair fractures of the tibial plateau, and extend autogenous bone grafts.17 Calcium phosphate cements have a fragility profile similar to traditional calcium phosphates. They have compressive strength in a range of 10— 100 mPa, a value, which is much higher than their tensile strength (1—10 mPa).3,32 This necessitates their use in either low or non-load bearing applications or in combination with metal implants. Norian SRS, a tricalcium phosphate cement, hardens approximately 12 h after injection, and its compressive strength is approximately 55 MPa. This is roughly 4—10 times greater than the average compressive strength of cancellous bone. The mechanical properties and the minimum degradation of glass-ceramic cylinders, found in a femoral bone diaphyseal critical defect study in rabbits, suggests that this substitute may be preferable in clinical situations of intense mechanical requirements or load bearing.13 Whether the adjacent host bone bed is osteoporotic or not, plays a significant role in local biomechanics. In addition, local biomechanics differ considerably if the scaffold material is placed in a relatively non-weight bearing area (i.e. to fill a bone cyst), in a contained or not bone defect, or it is used to reconstruct a segmental diaphyseal defect. The task of developing a device for bone replacement carries with it the additional requirement of high strength. Consequently, the scaffold should be designed to exceed the strength of the natural bone it replaces. 3D porous polymer scaffolds have demonstrated compressive mechanical strength and modulus within the normal ranges of trabecular bone properties. Pore sizes in the range of 150— 500 mm are optimal for interface activity, bone ingrowth, and implant resorption.32,33 Current research is directed toward understanding the change in strength that occurs as the scaffold is broken down over time in the body and is built up by ingrowth of new bone tissue.13 The purpose is to ensure that adequate strength is maintained throughout the period of bone remodelling.
Bone scaffolds: The role of mechanical stability and instrumentation
The role of internal fixation devices The influence of hardware fixation in conjunction with bone graft materials is a very complex issue, and there is little written in the literature. Hardware is very often necessary to provide sufficient stability to allow for graft incorporation. The exact extent to which the bone graft must be shielded from load by the hardware is virtually unknown to date. Internal fixation devices include, conventional plates and screws, locked compression plates (LCP), intramedullary nails, and external fixators. In joint reconstruction bone scaffolds can be protected by anti-protrusio rings, cups and cages, by cerclage wires or by distal fixation femoral systems in the case of proximal femoral bone loss and the need for its reconstruction. In general, plate—screw—bone constructs can act as load-sharing or load-bearing devices depending on fracture reduction and fragment interference. Neutralization plates function as load-sharing devices.5,12 These plates neutralize the effect of bending, rotational, and axial forces on the fracture site. In light of the fact that bone can withstand compression and metal can withstand tension, the plates should be placed in the tensile part of the equilibrium. The weakest link in the plate—screw— bone construct, both in neutralization and in dynamic compression plates, is the shear interface between the screw and the bone. In osteoporotic bone, improvements in plate fixation are directed to reduce the stress at the screw—bone interface by increasing the contact area between the screw and the bone. This can be done by the use of polymethyl methacrylate [PMMA] in the screw holes or by using HA coated screws. Another way to achieve this goal is by changing the stress at the screw—bone interface from shear stress (pullout) to compressive stress (locking plates).8 Conventional plates and screws may be (a) inadequate in achieving fixation in osteopenic or pathologic bone; (b) can lead to necrosis under the plate witch predisposes to infection; (c) may result in stress shielding which weakens the bone and increases the potential for refracture after device removal; and (d) create an environment where lack of stability may result to delayed union or non-union. Therefore, compression plating have limited use today, but may continue to be the method of choice for periarticular fractures, forearm fractures without bone loss where anatomic reduction is necessary to preserve motion, and certain types of non-unions where increasing stability can lead to union. In the presence of bone defects, where bone scaffolds may be used to reconstruct bone stock,
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there is increased need for a stable construct to effectively shield the graft material from excessive loading. Under these circumstances, plates are functioning as load-bearing devices. At the screw—bone interface locking plates convert shear stress to compressive stress and therefore fixation is improved because bone has much higher resistance to compressive stress than to shear stress. The difference in locked plates is that the strength of fixation equals the sum of all screw—bone interfaces rather than that of a single screw’s axial stiffness or pullout resistance as seen in unlocked plates.6 Furthermore locked plates act as ‘‘internal external fixators’’ (extremely rigid fixators) because of their very close proximity to the bone and fracture site. Consequently, locked plates may be the implant of choice in situations where bone scaffolds are used to regenerate bone stock loss.20 Buttress plates are load-bearing devices that act to counter shear forces at a fracture site by converting them to compressive axial forces. These plates are placed at the apex of the fracture. This technique is used to treat many intra-articular fractures as the tibial plateau fractures (Fig. 1a and b). Calcium phosphate has been used in depressed intra-articular tibial plateau fractures and compared favourably to cancellous bone grafts in biomechanical studies. In a study of 26 patients undergoing open reduction and internal fixation of displaced tibial plateau fractures, calcium phosphate was found to produce good outcomes. Because of the high mechanical strength of the cement, the authors allowed early weight bearing after a mean postoperative period of 4.5 weeks, with a range from 1 to 6 weeks. Despite early weight bearing, only 2 patients in this series suffered from a partial loss of reduction. Intramedullary nails are an example of internal splint fixation.24 The nail splints and bestows stability in a mode analogous to a tube within a tube.27 This type of fixation has unique biological and mechanical advantages over the plates and screws. The nails are placed near the neutral axis of bending of the bone, therefore being stronger than plates and can withstand loading for longer periods than plates until failure. Clinical results of closed intramedullary nailing have been proved superior to all other types of fixation in diaphyseal fractures and have been established as the method of choice.34 Unfortunately nailing, especially when intramedullary reaming is utilised, produces damage to the intramedullary blood supply of bone.23,26 Despite this theoretical disadvantage, closed techniques of reaming and nailing preserves the extraosseous and periosteal blood supply to bone and provide uneventful healing in the majority of cases.15
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Figure 1 (a) Anteroposterior knee X-ray showing a Schatzker type II tibial plateau fracture where Xenograft scaffold was used to support the depressed intra-articular surface and a buttress plate to counter shear forces at a fracture site by converting them to compressive axial forces. (b) Union of the fracture 4 months later.
In the case of segmental defects, although nailing provides an excellent biomechanical environment, the open technique needed for preparation of the host bone bed and insertion of bone scaffold devitalizes the blood supply in conjunction with the medullary blood supply damage caused by the
G.C. Babis, P.N. Soucacos reaming and nailing. In an experimental animal study of large (4—7 cm) diaphyseal defects, Meining20 found that intramedullary nailing used to shield a polylactide membrane scaffold caused avasularity in bone ends leading to poor bone regeneration. When the author used two locking plates applied orthogonally the membranes promoted spontaneous bone regeneration across the defect and clinical union.20 External fixators provide a relatively unstable fixation and it is used in various forms to treat open type III Gustilo fractures or infected non-unions. However, the stiffness of the construct depends on various factors such as the number and diameter of pins or half-pins, the distance of the pins from the fracture, the distance of the rod from the bone, etc. Circular external fixators as the Ilizarov frame have lower rigidity, especially in compression, and lower lateralmedial bending rigidity compared to HoffmannVidal half-pin frame. Nevertheless, lower rigidity and consequent micro-movement may be advantageous in providing axial loading to the regenerate bone.16 Cages in conjunction with autograft, allograft, and other scaffolds have been used extensively both in animal models and clinically in human spines to help achieve spinal fusion. Although only few of the experimental data are standardized through valid double blind controlled studies, there is general agreement that cages provide a biomechanical environment for scaffold materials to be incorporated and remodelled. In distal radial fractures the use of calcium phosphate combined with K-wire fixation was more stable than fixation with K-wires alone, but both were significantly less stable than external fixation that was augmented with calcium phosphate.14 Whereas internal or external fixation provides stress shielding for bone scaffolds, there are circumstances that the later enhance the stability of bone-instrumentation construct. In hip fractures calcium phosphate has been studied as adjunctive fixation in both femoral neck and intertrochanteric hip fractures especially in cases with extensive osteoporosis. In one prospective clinical study, patients with displaced femoral neck fractures were randomised in two groups. One group underwent closed reduction and fixation with 2 cannulated screws with augmentation using Norian SRS1 around the screws; in the other group only screws were used. Radiosteriometric analysis showed significantly better early stability of the fracture site at 1 and 6 weeks. Greater stiffness in specimens fixed with cannulated screws augmented with calcium phosphate was found in a biomechanical investigation compared to specimen fixed with screws alone. In a biomechanical investigation of simulated
Bone scaffolds: The role of mechanical stability and instrumentation
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There has been no mechanical failure so far, however longer follow up is needed for safe conclusions.
Biodegradable implants
Figure 2 Anteroposterior pelvis X-ray showing incorporation of the demineralized bone scaffold material 4 months after acetabular revision in the left hip.
unstable intertrochanteric hip fractures, specimens fixed with a sliding hip screw augmented with calcium phosphate had greater stiffness, stability, strength, and less shortening at the fracture site compared to those fixed with a sliding hip screw alone. Impaction grafting is an established method for bone reconstruction of severe bone loss both in the acetabulum and proximal femur at the time of revision arthroplasty. Originally described by Sloof et al.,30 for use in the acetabulum and later adapted for use in the femur, impaction grafting involves cementing a femoral component into compressed bone graft, usually morselized allograft.10 Instrumentation and biomechanics play a significant role in this application. The femoral stem, being polished and having a tapered shape, converts shear loads into radial compression forces (hoop stresses) while migrating distally. Graft remodelling has been documented in biopsy specimens taken during cement removal in some cases.21 In our department there is considerable experience with cotyloplasty, a method to restore the acetabular medial wall in CDH cases. The moselized allograft, placed in a well-vascularized bone bed and protected by the use of cement, regenerated consistently the inner wall of the acetabulum. This technique is currently extended also to revision cases with large contained defects. From 2001, 29 acetabular revisions with extended contained bone stock deficiencies were treated by meticulous preparation of the host bone bed, large quantities of allograft demiteralized bone matrix pressurized by reversed reaming and protected by the use of cementless HA coated antiprotrusio cups with a hook and external fins with screws. In all cases bone scaffolds were incorporated as seen in plain X-rays from the disappearance of scaffold-host reversed cement lines (Fig. 2).
Biodegradable implants can be fabricated in a way that at the same time play the roles of biomimetic scaffold while providing adequate stability and release bone morphogenetic proteins in a controlled manner so that the proper amounts are released over the right time period at the site of interest. The implant will enable healing by stabilizing the gap and offering a welcome environment for the body’s own bone cells. The implant will break down over time, as the patient’s own bone cells move in and produce replacement bone.
Conclusions In applications such as bone and cartilage tissue engineering, scaffold materials are often necessary to provide a platform on which cells can attach, grow, and proliferate. For load-bearing applications, these scaffolds must possess sufficient initial mechanical properties equivalent to healthy bone to prevent immediate failure upon implantation. In addition, scaffolds must be biodegradable, microporous, nano-structured biomimetic materials that are capable of transmitting changes in hydrostatic pressures that might influence bone remodelling in a manner similar to that of conventional bone grafts. Up to date bone scaffolds must be protected by the use of specific metallic implants, which should function until a prolonged period of time as load bearing devices. With the progress of bone scaffold incorporation and remodelling assuming mechanical properties, these implants will eventually become load shearing and therefore will be protected from implant failure.
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