1.2 Biology and biomechanics in bone healing
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1 Introduction
The biological and biomechanical basis of fracture management is covered in this chapter. We review how fractured bone behaves in different biological and mechanical environments, and how this influences the choice and method of treatment by the surgeon. Any surgical procedure may alter the biological environment and every fracture fixation alters the mechanical environment. These changes may have a profound effect on fracture healing and are determined by the surgeon, not the patient. Thus, it is essential that all trauma surgeons have a basic knowledge of the biology and biomechanics of fracture healing so they can make wise decisions in fracture management. This chapter offers a review for the active clinician rather than a pure scientific analysis. It describes the healing process in healthy populations with no discussion of impaired healing in conditions, such as diabetes. Despite worldwide research, much still remains unknown or controversial in this rapidly changing scientific field.
Our understanding of fracture treatment and healing has seen an important change in recent decades with the evolution of the AO principles [1, 2]. During the early phase of the development of these principles, the primary goal of surgical treatment was to provide the fracture with a motionless environment. High priority was given to precise fracture reduction and fixation with absolute stability with over emphasis on mechanical stability at the expense of biology. However, fracture treatment has evolved with recognition that both mechanics and biology are important. Precise reduction and absolute stable fixation is not required in every case and may come at a biological price. Indirect reduction takes advantage of the soft tissues and the blood supply to the bone fragments, which will come into alignment when traction is applied to the main fragments. This reduces surgical trauma and helps to keep the bone alive. Bone has evolved to heal with some movement between fragments and without each fragment being in contact. The concept of relative stability allows the surgeon to control the movement to allow healing while maintaining fracture reduction that will allow early rehabilitation and a good functional outcome for the patient. A more flexible fixation should encourage the formation of callus and indirect reduction will reduce operative trauma.
The main goal of fracture fixation is to achieve prompt and, if possible, full function of the injured limb. Although reliable fracture healing is only one element in functional recovery, it is essential for a good outcome. Fracture fixation is always a compromise that balances biology and biomechanics. It is often necessary to sacrifice some strength and stiffness of fixation, and the optimal implant is not necessarily the strongest or the stiffest available.
It is not the purpose of osteosynthesis to permanently replace a fractured bone but to provide temporary support, allowing early functional rehabilitation with healing in an appropriate anatomical position.
Under extreme conditions, the mechanical requirements may gain precedence over biological demands and vice versa. Similarly, the choice of implant material is a trade-off, eg, the mechanical strength and ductility of steel versus the electrochemical and biological inertness of titanium. The surgeon decides which combination of technology and procedure best fits his experience, environment, and, in particular, the demands of the patient.
2 Characteristics of the patient
When considering the personality of a fracture, the first critical element is the characteristics of the patient (see chapter 2.1). Clinical decisions must always take into account the patient′s age, expectations, comorbidities, and psychosocial factors. Inherent biological deficits may need to be overcome, or expectations must be lowered when a favorable outcome is less likely. No decision can be made solely on the basis of radiological evaluation.
3 Characteristics of bone
Bone is a scaffold that supports and protects soft structures and enables locomotion and mechanical functioning of the limbs.
The most important mechanical characteristics of bone are its stiffness (bone deforms only a little under load) and strength (bone tolerates high load without failure).
In considering a fracture and fracture healing, the brittleness of bone is of special interest. Bone is a strong material. However, it breaks under small deformation. This means that bone behaves more like glass than like rubber. Therefore, at the onset of natural fracture healing, bone cannot bridge a fracture gap that is repeatedly subject to excessive displacement. For an unstable or flexibly fixed fracture (relative stability), a sequence of biological events—mainly the formation of first a soft and then a hard callus—helps to reduce the strain and deformation of the repair tissues and thus increase stability (see section 4.3.3 in this chapter). Resorption at the fracture ends initially increases the fracture gap and this reduces the strain at the fracture site. The lower-strain environment promotes formation of bridging callus, which then increases the mechanical stability of the fracture. Once the fracture is solidly bridged, full bone function is restored. Internal remodeling then restores the original bone structure, a process that can take years (see chapter 5.2).
4 Fracture of bone
A fracture is always the result of single or repetitive overload. The fracture occurs within a fraction of a millisecond. It results in predictable damage to soft tissues due to rupture and an implosion-like process. Rapid separation of fracture surfaces creates a void (cavitation) and results in severe soft-tissue damage ( Video 1.2-1 ).
4.1 Mechanical and biochemical effects
A fracture produces a loss of bone continuity that results in pathological deformation, loss of the support function of bone, and pain. Surgical stabilization may restore function immediately and alleviate pain. Thus, the patient regains pain-free mobility allowing early rehabilitation and reducing the risk of conditions like complex regional pain syndrome (see chapter 4.7).
Fracture of bone ruptures the blood vessels within bone and periosteum. Spontaneously released biochemical factors help to induce bone healing. In fresh fractures these agents are effective and scarcely need any boost. The role of surgery should be to guide and support this healing process.
4.2 Fracture and blood supply
Although a fracture is a purely mechanical process, it triggers biological reactions, such as bone (callus) formation and bone resorption. These two processes depend on an intact blood supply. The following factors influence blood supply at the fracture site and have an immediate bearing on the surgical procedure:
Mechanism of injury: The amount, direction, and concentration of forces at the fracture site will determine the fracture type and associated soft-tissue injuries. As a result of the displacement of fragments, periosteal and endosteal blood vessels rupture and the periosteum is stripped. Cavitation and implosion of the fracture cause additional soft-tissue damage.
Initial patient management: If rescue and transportation take place without splinting of fractures, motion at the fracture site will add to the initial damage.
Patient resuscitation: Hypovolemia, hypoxia, and coagulopathy will increase damage to injured bone and soft tissues, and must be corrected early in patient management.
Comorbidities: Such as peripheral vascular disease and diabetes.
Surgical approach: Surgical exposure of the fracture will invariably result in additional damage [3]. This can be minimized by a thorough knowledge of anatomy, careful preoperative planning, and meticulous surgical technique.
Implant: Considerable damage to bone circulation may result not only from the surgical trauma but also from the contact between implant and bone [4]. Plates with a flat undersurface (eg, DCP) have a large area of contact; the LC-DCP, which is undercut, was designed to reduce this contact area [5]. However, the extent of the contact also depends upon the relationship of the radii of transverse curvature of the plate and the bone. When the radius of curvature of the undersurface of the plate is larger than that of the bone, bone-plate contact may be in a single longitudinal line, which reduces the advantages of the LC-DCP (and also the locking compression plate [LCP] when used as compression plate) compared with the flat undersurface of the DCP ( Fig 1.2-1a ). If the situation is reversed and the plate has a smaller radius of transverse curvature than the bone, there will be longitudinal contact at both edges (two-line contact), and the lateral undercuts of the LC-DCP and LCP (when used as compression plate) will significantly reduce the area of contact ( Fig 1.2-1b–d ).
Consequences of trauma: Elevated intraarticular pressure reduces the epiphyseal bone circulation, especially in young patients. The increase in hydraulic pressure (produced by an intracapsular hematoma) has been shown to reduce blood supply to the epiphyseal bone when the growth plate is still open.
Dead bone can only be revitalized by removal and replacement (creeping substitution through osteonal or lamellar remodeling), a process that takes a long time to complete. It is generally accepted that necrotic tissue (especially bone) predisposes to infection and sustains it (see chapter 5.3). Another effect of necrosis is the induction of internal (Haversian) remodeling. This allows replacement of dead osteocytes but results in temporary weakening of the bone due to transient porosis, which is an integral part of the remodeling process. This is often seen immediately beneath plates and can be lessened by reducing the contact area of the plate (eg, LC-DCP and LCP), which fosters the periosteal blood supply and reduces the volume of avascular bone.
An immediate reduction of bone blood flow has been observed after fracture or osteotomy, with the cortical circulation in the injured parts of the bone being reduced by nearly 50% [6]. This reduction has been attributed to a physiological vasoconstriction in both the periosteal and the medullary vessels as a response to trauma [7]. During repair of a fracture, however, there is increasing hyperemia in the adjacent intraosseus and extraosseus circulation, reaching a peak after 2 weeks. Thereafter, blood flow in the callus area gradually decreases again. There is also a temporary reversal of the normal centripetal blood flow after disruption of the medullary system.
Microangiographic studies [8, 9] have demonstrated that much of the vascular supply to the callus area is derived from the surrounding soft tissues ( Fig 1.2-2 ), a good reason not to strip any soft tissues.
Perfusion of callus is of utmost importance and may determine the outcome of healing. Bone can only form when supported by a vascular network and cartilage will not persist in the absence of sufficient perfusion. However, this angiogenic response depends upon both the method of treatment and the induced mechanical conditions:
The vascular response appears to be greater after more flexible fixation, perhaps due to a larger volume of callus.
High strain in tissue, caused by excessive instability, reduces the blood supply, especially in the fracture gap.
The operative procedure during internal fixation of fractures alters the hematoma and soft-tissue blood supply. Following intramedullary reaming, endosteal blood flow is reduced but there is a rapid hyperemic response if reaming has not been excessive.
Reaming for intramedullary nails results in a delayed return of cortical perfusion, depending on the extent of reaming [10]. Reaming does not affect perfusion within the fracture callus, as blood supply to the callus is mostly from the surrounding soft tissues [11].
In addition to the wider exposure of the bone, larger bone-implant contact will result in a reduction of bone perfusion, as bone receives its blood supply through the periosteal and endosteal lining.
Damage to the blood supply is minimized by avoiding direct fragment manipulation, minimally invasive surgery, and the use of external or internal fixators [12, 13].
4.3 Biology of fracture healing
Fracture healing can be divided into two types:
Primary or direct healing by internal remodeling
Secondary or indirect healing by callus formation
Direct (primary) bone healing occurs only with absolute stability and is a biological process of osteonal bone remodeling. Note that primary bone healing was not the goal when the technique of absolute stability was developed by Danis: the aim was anatomical reduction and stable fixation to allow early rehabilitation. Primary bone healing was observed as a by-product of this method of fracture fixation. Indirect (secondary) bone healing occurs with relative stability (flexible fixation methods) and is the normal way that broken bones have evolved to heal. It is similar to the process of embryological bone development and includes both intramembranous and endochondral bone formation. In diaphyseal fractures, it is characterized by the formation of callus.
Indirect (secondary) bone healing can be divided into four stages:
Inflammation
Soft callus formation
Hard callus formation
Remodeling
Although the stages have distinct characteristics, there is a seamless transition from one stage to another; they are determined arbitrarily and have been described with some variation.
4.3.1 Inflammation
After fracture, the inflammatory process starts immediately and lasts until fibrosis, cartilage, or bone formation begins (1–7 days after fracture). Initially, there is hematoma formation and inflammatory exudation from ruptured blood vessels ( Fig 1.2-3a ). Bone necrosis is seen at the ends of the fracture fragments. Injury to the soft tissues and degranulation of platelets results in the release of powerful cytokines that produce a typical inflammatory response, ie, vasodilatation and hyperemia, migration and proliferation of polymorphonuclear neutrophils, macrophages, etc. Within the hematoma, there is a network of fibrin and reticulin fibrils; collagen fibrils are also present. The fracture hematoma is gradually replaced by granulation tissue. Osteoclasts in this environment remove necrotic bone at the fragment ends.
4.3.2 Soft callus formation
Eventually, pain and swelling decrease and soft callus is formed ( Fig 1.2-3b ). This corresponds roughly to the time when the fragments are no longer moving freely, approximately 2–3 weeks after fracture.
At the end of soft callus formation, stability is adequate to prevent shortening, although angulation at the fracture site may still occur.
The soft callus stage is characterized by the growth of callus. The progenitor cells in the cambial layer of the periosteum and endosteum are stimulated to become osteoblasts. Intramembranous, appositional bone growth starts on these surfaces away from the fracture gap, forming a cuff of woven bone periosteally, and filling the intramedullary canal. In-growth of capillaries into the callus and increased vascularity follows. Closer to the fracture gap, mesenchymal progenitor cells proliferate and migrate through the callus, differentiating into fibroblasts or chondrocytes, each producing their characteristic extracellular matrix and slowly replacing the hematoma [14].
4.3.3 Hard callus formation
When the fracture ends are linked together by soft callus, the hard callus stage starts ( Fig 1.2-3c–e ) and lasts until the fragments are firmly united by new bone (3–4 months). As intramembranous bone formation continues, the soft tissue within the gap undergoes endochondral ossification and the callus is converted into rigid calcified tissue (woven bone). Bone callus growth begins at the periphery of the fracture site, where the strain is lowest. The production of this bone reduces the strain more centrally, which in turn forms bony callus. Thus, hard callus formation starts peripherally and progressively moves toward the center of the fracture and the fracture gap. As the fracture gaps narrows, the strain increases and the final gap is bridged by osteoblasts that line up in a spiral formation, like a spring, to reduce strain and allow bone formation. The initial bony bridge is formed where strain is lowest at the periphery of the callus or within the medullary canal, away from the original cortex. Then, by endochondral ossification, the soft tissue in the gap is replaced by woven bone that eventually joins the original cortex.
4.3.4 Remodeling
The remodeling stage ( Fig 1.2-3f ) begins once the fracture has solidly united with woven bone. The woven bone is slowly replaced by lamellar bone through surface erosion and osteonal remodeling. This process may take anything from a few months to several years. It lasts until the bone has completely returned to its original morphology, including restoration of the medullary canal.
4.3.5 Growth factors
The sequence of events during bone healing is tightly regulated by spacial and temporal expression of a number of growth factors and biochemical agents that are released by the injured tissue. Since their discovery in the 1960s by Marshall Urist, bone morphogenetic proteins (BMPs) have been shown to be potent inducers of bone formation [15]. Bone morphogenetic proteins are members of the transforming growth factor-beta superfamily; there are about 20 mammalian BMPs known to date. These factors offer the potential for the enhancement of fracture repair or reconstruction of bone defects. In clinical practice, BMP-2 is the most frequently used, although it is estimated that up to 85% of use is off-label. Bone morphogenetic protein-2 is indicated for spinal fusion procedures in skeletally mature patients with degenerative disc disease (DDD) at one level from L2-S1, in combination with a spinal fixation device. In 2004, the US Food and Drug Administration (FDA) approved BMP-2 for treating open tibial shaft fractures and in 2007, BMP-2 was approved by the FDA for sinus lift and local ridge augmentation. The recombinant protein is often applied in combination with a collagen scaffold.
While BMPs may lead to robust bone formation, it is crucial to be aware of the numerous potential adverse effects, such as ectopic bone formation, and these factors should be used with caution.
4.3.6 Differences in healing between cortical and cancellous bone
As opposed to indirect healing in cortical bone, healing in cancellous bone occurs without the formation of significant external callus. After the inflammatory stage, bone formation is dominated by intramembranous ossification. This has been attributed to the tremendous angiogenic potential of trabecular bone as well as the fixation used for metaphyseal fractures, which is often more stable. In unusual cases with substantial interfragmentary motion, intermediary soft tissue may form in the gap but this is usually fibrous tissue that is soon replaced by bone.
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