This article focuses on the understanding of the biochemistry and surgical application of bone substitute materials (BSMs) and particularly the newer calcium phosphate materials that can form a structural orthobiologic matrix within the metaphyseal components of the periarticular bone. Six characteristics of BSMs are detailed that can be used as a guide for the proper selection and application of the optimal BSM type for periarticular fracture repair. These 6 characteristics of BSMs are divided into 2 pillars. One pillar details the 3 biochemical features of BSMs and the other pillar details the 3 surgical application properties.
Key points
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This article focuses key questions that can lead to the understanding and application of bone substitute materials (BSMs) that form a structural orthobiologic matrix within the metaphyseal components of the periarticular fracture.
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These 6 characteristics of BSMs are a rapid way for the surgeon to categorize the properties of BSMs and provide an algorithm for the selection of the optimal BSM.
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Advances in BSMs are synergistic with minimally invasive surgery (MIS) and have the potential for significant impact on orthopedic patients’ health and socioeconomic viability after injury.
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Calcium phosphate cements in combination with MIS techniques and implants can enhance rehabilitation and recovery and lead to the realization of the vision of immediate postoperative load bearing of our patients with periarticular fracture.
Introduction
The past 35 years have been unprecedented as a time of innovation in orthopedic surgery with regard to surgical techniques, procedures, and metal alloy biomaterial fabrication with patients benefitting from reduced deformity, earlier mobilization, and decreased permanent disability after skeletal injury and disease.
Minimally invasive surgery (MIS) allows for safe insertion of sophisticated implants while causing the least possible trauma to the soft tissue environment of injury and to patients. MIS is still evolving through advances in incision design, surgical implants and instruments with the aid of a wide variety of imaging technologies (intraoperative computed tomographic scanning and MRI) as well as the more recent development of computer-assisted technology.
When bone is damaged by crush or loss of tissue, surgical stabilization and subsequent bone regeneration may be impossible without the addition of materials to address the bone defect. Bone substitute materials (BSMs) are evolving in parallel with advances in MIS to meet patients’ demands for more rapid recovery from musculoskeletal injury permitting earlier weight bearing, leading to earlier return to work and recreation.
This article focuses on the understanding and application of BSM and particularly the newer calcium phosphate materials that can form a structural orthobiologic matrix within the metaphyseal components of the periarticular fracture. Primarily, there are 6 characteristics of BSMs that can be used as a guide for the proper selection and application of the optimal BSM type for periarticular fracture repair, and these are discussed in detail.
Introduction
The past 35 years have been unprecedented as a time of innovation in orthopedic surgery with regard to surgical techniques, procedures, and metal alloy biomaterial fabrication with patients benefitting from reduced deformity, earlier mobilization, and decreased permanent disability after skeletal injury and disease.
Minimally invasive surgery (MIS) allows for safe insertion of sophisticated implants while causing the least possible trauma to the soft tissue environment of injury and to patients. MIS is still evolving through advances in incision design, surgical implants and instruments with the aid of a wide variety of imaging technologies (intraoperative computed tomographic scanning and MRI) as well as the more recent development of computer-assisted technology.
When bone is damaged by crush or loss of tissue, surgical stabilization and subsequent bone regeneration may be impossible without the addition of materials to address the bone defect. Bone substitute materials (BSMs) are evolving in parallel with advances in MIS to meet patients’ demands for more rapid recovery from musculoskeletal injury permitting earlier weight bearing, leading to earlier return to work and recreation.
This article focuses on the understanding and application of BSM and particularly the newer calcium phosphate materials that can form a structural orthobiologic matrix within the metaphyseal components of the periarticular fracture. Primarily, there are 6 characteristics of BSMs that can be used as a guide for the proper selection and application of the optimal BSM type for periarticular fracture repair, and these are discussed in detail.
Bone
Bones comprising the skeletal system are dynamic organs with mineral, cellular, molecular, and vascular components. Bone is a “fiber-reinforced composite of a biological origin, in which nanometer-sized hard inclusions are embedded into a soft protein matrix.” Bone is produced by specialized interacting cells known as a bone metabolic unit, which consist of osteoclasts, osteoblasts, and osteocytes, working together to form bone structural units (BSUs). These BSUs are the building blocks of the bone lamellae and subsequent composites of cortical and cancellous bone that form the specific skeletal bone. These units have a finite life span with a range of 3 to 20 years depending on the metabolic requirements of the host and structural demands on the bone. During fracture healing, woven bone is produced initially and is converted to the more resilient lamellar bone by a process known as bone remodeling. Normal bone remodeling is a coordinated cyclic process of bone resorption (osteoclasts) and bone formation (osteoblasts). The main functions of bone remodeling are reshaping and replacement of bone during growth and following injury and trauma; preserving bone strength by removing old (micro) damaged bone and replacing it with newer mechanically stronger bone; and involvement in calcium and phosphate homeostasis. Along with remodeling, bone has the capacity of regeneration, which is a tightly regulated process of bone formation evidenced in fracture healing and is associated with continuous remodeling throughout adult life. Bone’s capability for regeneration is the key to the utility of bioavailable calcium phosphate cements (CPCs) in critical size defects and reinforcement/augmentation of internal fixation in compromised bone.
Bone has several unique attributes, including its physical properties of flexible rigidity, optimal strength to weight ratio, ability for self-repair through osteogenesis after injury, and contribution to the metabolic stability of the body as its primary reserve for vital minerals, including calcium, phosphate, magnesium, sodium, and carbonate. Each bone is individually structured for its respective contribution to mobility, anchorage and protection of the soft tissues, and physical interaction with a person’s environment. When bone is damaged by injury or disease, such that its’ normal repair/regeneration cycle is compromised, augmentation with synthetic BSMs may assist in prevention of deformity and nonunion (in conjunction with modern surgical implants and techniques).
Diamond concept
As already stated, bone possesses a considerable capacity for regeneration following trauma. A complex pathway of both physiologic and biomechanical interactions are required in order for fracture healing to occur. These processes can be illustrated using the Diamond Concept. The Diamond Concept of fracture healing relates the interaction of osteogenic cells, osteoinductive signals, and osteoconductive scaffolds with surgical reconstruction with implants in achieving bone repair ( Fig. 1 ). The Diamond concept of fracture repair groups the components required for successful fracture healing. This article focuses on one particular aspect of the Diamond concept, the osteoconductive scaffold group.
The osteoconductive group
BSMs represent the osteoconductive component of the Diamond concept paradigm and at this time should not be considered osteoinductive or cell delivery systems (new developments to attain these attributes are in the research arena). Although they lack the osteoinductive/osteogenic properties, they promote migration, proliferation, and differentiation of bone cells for bone regeneration. As such, they provide structural material, although not necessarily structure to the fracture site. Optimally, they act as matrix materials for the ingrowth of new bone while minimizing dead space and the possibility of connective tissue replacement of the bone defect with scar formation.
BSMs are usually synthetic in that they are produced from sintering chemically formed compounds or through precipitation wet chemical route. As these synthetic BSMs are chemically created, their physical properties are easily altered and reproduced. The microstructure of the synthetic BSMs can be optimized to mimic human cancellous bone by adjusting the chemical formulations as well as optimizing its osteoconductive properties. Within the United States, the Food and Drug Administration (FDA) has limited the regulatory clearance of most of these synthetic BSMs to being used when the void is minor or non–load bearing when used in isolation. In Europe, regulatory clearances have permitted third-generation premix CPCs and augmented fixation devices to be widely available.
There are several synthetic BSMs currently available, including hydroxyapatite (HA), tricalcium phosphate (TCP), CPCs, and glass ceramics. HA is similar to the mineral component of natural bone, is a naturally occurring mineral form of calcium apatite, and is considered extremely biocompatible. Synthetic HAs in their many forms are one of the most common BSMs used. TCP, another common compound of bone, acts efficiently as an osteoconductive scaffold and is more soluble and less crystalline than HA allowing it to be more readily resorbed. TCP exists in 2 forms: alpha (α) and beta (β) TCP. α-TCP is more soluble than β-TCP and resorbs faster in vivo.
Biphasic calcium phosphates are produced by combinations of calcium phosphates, such as HA and TCP. Its rate of resorption depends on the amount of each used to generate the BSM.
Calcium sulfates are also often used as a BSM. Calcium sulfates can dissolve and resorb extremely quickly, usually within a period of weeks, which renders it unsuitable for instances whereby long-term scaffolding is required for growth.
Longer-acting osteoconductive BSMs address the clinical problems of insufficient bone quality or quantity. In intraarticular fractures, proper placement of flowable CPCs may retard the influx of synovial fluid, which contains antiangiogenic factors that may compromise revascularization of the fracture site. However, there are critical factors the orthopedic surgeon needs to be aware of to ensure safe and effective use of these materials. Common clinical concerns include
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Infection/contamination at the injury site
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Neoplasm/cystic processes within Osteolytic voids at the injury site
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The extent of surgically induced defects from osteotomies and arthroplasty as to gross structural stability
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Reconstruction of open fractures with bone extrusion and loss
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Analysis of impaction loss with periarticular metaphyseal of the intraarticular components of cartilage and soft tissues combined with the cancellous and cortical bone loss
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Osteopenia compromising bone implant anchorage
Implant stabilization and augmentation: polymethyl methacrylate versus bone substitute materials
The initial concepts of implant stabilization at the interface of the bone implant junction were developed for total joint arthroplasty by Charnley in 1958. Since then there has been an abundance of material specifically developed for implant stabilization and augmentation. For a surgeon, the selection of which material to use for an indication, the method to prepare it, and how to place it in the optimal position are critical factors in whether to choose products composed of polymethyl methacrylate (PMMA), BSMs, or other augmentation materials. Fig. 2 illustrates and compares the differences between bone cement (PMMA) and CPCs.
Bone cement or PMMA is a biostable polymer of carbon (C 5 O 2 H 8 ) n , also known as acrylic, that undergoes polymerization when activated as opposed to the crystallization process of the calcium orthophosphate cements and has no potential for remodeling. Harrington and Johnston and Bartucci and colleagues reported the use of PMMA in fracture care in osteoporotic fractures, but initial results were compromised by the inhibition of fracture healing. Additionally, difficulties with extravasation and requisite high-pressure injection methods discouraged widespread use in nonpathologic fractures.
Characteristics of bone substitute material
Synthetic BSMs are complex molecules and composites unlike any other implants surgeons use with regard to function, preparation, handling, and placement. For a surgeon to use these materials in surgery, the selection of which material to be used and how to prepare it and place it in the optimal position are as critical as knowing what size and type of implant (ie, plate) as well as the number and location of screws to use. For example, in younger patients, the option of complete biological conversion to new bone is most desirable, whereas, in older patients, a longer stable mechanical structure may be desirable because of the impaired osteogenic potential in the older host. In cases of bacterial contamination, calcium sulfates may be used alone or in combination with antibiotics at the surgeons’ discretion to help control contamination as they dissolve with no residual material. CPCs should not be used in contaminated wounds as they may become foci for bacterial biofilm production.
The analysis to determine the optimal application of a BSM requires an understanding of the 6 characteristics. These 6 characteristics of BSMs can be divided into 2 pillars:
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The biochemistry of BSMs
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The surgical application of BSMs ( Table 1 )
Table 1
The 6 characteristics of bone substitute materials
Biochemistry
Surgical Application
Molecular formulae
Material preparation
Morphology
Mechanical properties
Metabolism
Material placement
The characteristics of BSMs are shown here divided into 2 pillars: the biochemistry pillar encompassing molecular formulae, morphology, and metabolism and the surgical application pillar containing the mechanical properties, material preparation, and material placement.
The biochemistry pillar encompasses molecular formulae, morphology, and metabolism; the surgical application pillar includes the mechanical properties, material preparation, and material placement, all of which are discussed in detail later.
Biochemistry: pillar I
Biochemistry looks at structure, function, and interaction of biological macromolecules within a host organism. In this case, it is BSMs’ structure and function as a bone remodeler that is critical. In examining the molecular formula, morphology, and porosity of BSMs, a greater analysis can be made as to how these BSMs will function in their role as bone remodelers within the body and the properties they will contribute to the material used by the surgeon. Investigating BSMs’ metabolism reveals the conversion of their biological signals into downstream process and applications. This information is a key piece of information the surgeon requires when determining what material to use, particularly in fracture healing processes.
Molecular Formulae
The molecular formulae of the BSM is most commonly one of 3 types:
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A combination of calcium sulfate and granular hydroxyapatite
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A calcium sulfate
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Calcium phosphate composite
The molecular formulae of human bone mineral is expressed as Ca1 0-x (M) x (PO4) 6-x (HPO4,CO3) x (OH) 2-x and is different from granular HA as it is populated with metal ions, most commonly magnesium and carbonate.
The calcium sulfates, CaSO 4 , are simple ionic salts. These materials rapidly dissolve in water releasing calcium ions and produce a pH acidic shift due to the sulfate ions combining with hydrogen. Therefore, calcium sulfate materials do not remodel through cell-mediated processes rather they dissolve readily independent of bone ingrowth or repair.
Calcium phosphates are covalently bound molecules and are more stable in an aqueous environment. They vary from simple Ca 3 (HPO 4 ) molecules to complex biomimetic molecular forms very similar to human bone mineral.
Silicates may be added to calcium phosphates but their effect on bone healing has been a matter of some debate. Early work done by Carlisle suggests that silicon is present during new bone formation in the early stages of biomineralization but it decreases to a negligible amount as the final physiologic HA is formed. This work has led researchers to consider silicon as an additive to HA to induce a faster remodeling response. In more recent work, Patel and colleagues advocated the use of silicon substitute TCP; their early preclinical work demonstrated an increase in the speed and quality of the bone repair process. The mode of action for the silicon substituted HA materials as proposed by Pietak and colleagues show that the presence of the ion modifies the surface chemistry of the material through modification of the surface microstructure giving increased solubility rates rather than any metabolic cell-based interaction. Despite the preclinical research and the many claims made for silicon substituted biomaterials’ increased efficacy, there is no substantial clinical evidence showing an increased healing that would be relevant to a surgeon.
The molecular formulae of these materials are important because as advanced calcium phosphates’ molecular formulae more closely resemble that of human bone mineral, then the biocompatible bone matrix substitute materials formed are capable of maintaining structure until the required remodeling occurs by bone metabolic units.
Morphology
The term morphology simply means the particular shape, form, or structure of the material. In the case of BSMs, the form and shape can include flowing self-setting cements, irregular granules, regular-shape blocks (wedges, discs, and so forth), and putties. In the case of augmenting fractures in MIS surgery, the most advantageous form is the flowable self-setting CPCs. These materials have the unique ability to be a flowing viscous liquid allowing surgical delivery and filling of a bone void through a small entry hole in the bone. Once in place, the materials then undergo a setting process and move from a liquid phase through a paste phase to finally set as a solid phase with enough mechanical strength to maintain volume and remain where placed.
Flowing calcium phosphate materials are available with enhancements provided by additives to induce pore formation of size and interconnectivity to encourage enhanced surface area and revascularization capability after crystallization is completed. These flowing CPCs are generally non-Newtonian fluidic materials with atypical fluid behavior when compared with water (a Newtonian material) in that their viscosity and ability to flow are time dependent and inversely related to insertion pressure and the reciprocal shear that force induces. Counterintuitively, pushing harder on an injection device for a non-Newtonian CPC will reduce its capability to flow; if a critical insertion force is exceeded, the CPC will phase separate (separation of the hydration fluid and the powder) inactivating the CPC and preventing further flow.
With MIS techniques, the bone defect is closed before insertion of the BSM by the fracture reduction. The BSM must be contained within the bone for optimal function and metabolism. When the surgeon tries to inject the BSM with a needle or cannula, a pressure gradient inside the closed defect develops from residual blood and debris within the fracture (Venturi effect of pressure equalization with noncompressible fluids in closed chambers). This pressure gradient results in extrusion of the material at the entry site and incomplete fill ( Fig. 3 ). Larger cannulas may be used, but the material may leak out into the soft tissues from the holes created. A secondary problem may be extrusion of the BSM into the joint or out of the fracture zone in comminuted fractures when one tries to increase the pressure of injection. This extrusion may be the primary reason for slow adoption of BSM in the past despite the level of evidence for its superiority over cancellous autograph and allograft bone tissue with regard to structural stability of the articular reduction.
