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Fracture Healing Overview
Definition/Introduction
Bone fracture healing is an intricate and dynamic regenerative process that aims to restore damaged bone to its pre-injury structure and cellular composition.[1] A fracture represents a disruption in the structural continuity of the bone cortex and is typically accompanied by varying degrees of injury to the surrounding soft tissues. After a fracture occurs, the body initiates secondary bone healing, which progresses through a series of overlapping stages. The first stage is hematoma formation, in which bleeding from disrupted vessels creates a clot at the fracture site. This is followed by granulation tissue formation, as inflammatory cells and fibroblasts migrate to the area and begin to form a soft tissue scaffold. Next, a bony callus develops as cartilage and immature bone stabilize the fracture. Finally, bone remodeling gradually replaces the callus with mature lamellar bone, restoring the bone’s original structure and mechanical strength over time.
The type of fracture healing is governed by the achieved mechanical stability at the fracture site and, consequently, the strain. An appropriate mechanical stimulation, such as strain, facilitates tissue formation at the bony ends. The magnitude of the strain involved dictates the biological behavior of the cells involved in the healing process and, consequently, the type of bone healing.[2][3][4] Primary bone healing ensues with mechanical strain below 2%, whereas secondary bone healing ensues when the mechanical strain is between 2 and 10%.[5][6][7][8] In contrast, a strain >10% results in non-union or delayed union.[5][6][9][10]
There are 2 main modes of bone healing; primary bone healing is dictated by absolute stability constructs that achieve a mechanical strain below 2%. It is an intramembranous bone healing that occurs through Haversian remodeling. The other type is secondary bone healing, which occurs with non-rigid fixation modalities such as braces, external fixation, bridging plates, intramedullary nailing, etc. These fixation modalities achieve a mechanical strain between 2-10%. And it occurs via endochondral bone healing. Bone healing can involve a combination of primary and secondary processes, depending on the stability of the construct. Failed or delayed healing can affect up to 10% of all fractures and can result from factors such as comminution, infection, tumor, and disrupted vascular supply. In this top, we work through each of these steps in detail before touching on primary healing, factors that affect fracture healing, and methods to stimulate fracture healing.[1][11]
Issues of Concern
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Issues of Concern
Fracture healing starts with an anabolic phase in which stem cells are recruited and differentiate, leading to increases in skeletal and vascular tissue volume. A cartilaginous callus forms at the fracture site, whereas at the periphery of this callus, the periosteum swells, and the primary bone formation starts.[12] Simultaneously with cartilaginous callus formation, the cells involved in angiogenesis are recruited and differentiated in the nearby muscle mass. With further progression of chondrocyte differentiation, the extracellular matrix is mineralized, and the chondrocytes undergo apoptosis. This is followed by a catabolic phase in which cartilage resorption ensues, resulting in reductions in tissue and callus volume.[1]
Fracture healing is complex, and it involves the following stages: hematoma formation, granulation tissue formation, callus formation, and bone remodeling. However, there is considerable overlap between these stages. Principal cells and their secretions are involved in the healing process, in which the mesenchymal stem cells play a pivotal role. They are derived mainly from 2 major sources: the periosteum and the endosteum. Others involved include inflammatory cells, endothelial cells, fibroblasts, osteoblasts, and osteoclasts.[1][13]
Hematoma Formation:
Hematoma formation occurs immediately after injury and is a key step in fracture healing. The blood vessels supplying the bone and periosteum are disrupted during the fracture, causing a hematoma to form at the fracture site, which is rich in hematopoietic cells. The hematoma clots and forms the temporary frame for subsequent healing. An adequate number of MSCs is recruited at the fracture site from the nearby tissues and the circulation.[14][15] MSCs express matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which both influence MSCs' migration capacity.[16][17][18]
Macrophages, neutrophils, and platelets release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), bone morphogenetic proteins (BMPs), platelet-derived growth factors (PDGF), transforming growth factor beta (TGF-Beta), vascular endothelial growth factor (VEGF), and interleukins (IL-1, IL-6, IL-10, IL-11, IL-12, IL-23). These cytokines further stimulate essential cellular biology at the fracture site.
Granulation Tissue Formation (Primary or fibrocartilaginous callus):
Granulation tissue formation occurs within 2 weeks of injury and provides provisional stability. Platelets are recruited to the fracture site. Among the products secreted by platelets are fibronectin (FN), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β), which collectively trigger an inflammatory response. Subsequently, other mesenchymal and inflammatory cells are recruited to the fracture site, including fibroblasts and endothelial cells, resulting in fibrin-rich granulation tissue formation and angiogenesis.[19] The granulation tissue withstands the greatest strain prior to failure during the healing process. Mesenchymal stem cells begin to differentiate (driven by BMPs). As a result, chondrogenesis begins, laying down a collagen-rich fibrocartilaginous network spanning the fracture ends, with a surrounding hyaline cartilage sleeve. At the same time, adjacent to the periosteal layers, the osteoprogenitor cells lay down a layer of woven bone. The release of cytokines such as VEGF and TGF-β induces angiogenesis at the fracture site.[20] Angiogenesis is critical for the morphological structure of bone-bridging tissue and for the overall fracture-healing process. Delayed union or non-union could result from deficient angiogenesis.[21][22]
Bony Callus Formation:
If the bone ends are not in direct contact, a soft bridging callus forms to stabilize the fracture. The endosteum and periosteum serve as the primary sources of fibroblasts involved in fracture healing.[23] These fibroblasts are critical because they secrete key matrix components, including collagen, elastic and mesh fibers, and glycoproteins. Under the influence of bone morphogenic proteins (BMPs) and fibroblast growth factors (FGFs) released at the fracture site, fibroblasts differentiate into osteoblasts.[24][25] This differentiation is accompanied by increased levels of alkaline phosphatase (ALP), total calcium content, and the expression of osteogenic marker genes, including integrin-binding sialoprotein (IBSP), runt-related transcription factor 2 (Runx2), and other osteoblast-associated transcription factors.[26][27] Together, these processes form the bony callus that bridges the fracture and initiates the restoration of bone structure.
The cartilaginous (soft) callus begins to undergo endochondral ossification, and a medullary callus further supports the bridging soft callus. RANK-L is expressed, stimulating further differentiation of chondroblasts, chondroclasts, osteoblasts, and osteoclasts. As a result, the cartilaginous callus is resorbed and begins to calcify. Subperiosteally, woven bone continues to be laid down. The newly formed blood vessels continue to proliferate, allowing further migration of mesenchymal stem cells. At the end of this phase, a hard, calcified callus of immature bone forms. Bone callus formation is dependent upon appropriate relative motion between fracture fragments.[28][29]
Bone Remodelling:
Bone remoderling can continue for months to years after the clinical union. This involves a complex interaction of signaling pathways, including BMP, fibroblast growth factor (FGF), parathyroid hormone-related peptide (PTHrP), and Indian hedgehog (Ihh). All of which are involved somehow in the differentiation of the appendicular skeleton. The hypertrophic chondrocytes express type X collagen while the extraarticular matrix is being calcified, then degraded by proteases. Cartilaginous calcification occurs at the junction of the maturing chondrocytes and newly forming bone. Then the chondrocytes undergo apoptosis, and new vessels form as VEGF is further released.
Osteoclasts have the capacity for bone matrix resorption, while osteoclasts' differentiation and activity are coordinated by osteoblasts.[30][31] Osteoblasts express the receptor activator of nuclear factor-B ligand (RANKL), which interacts with the receptor activator of nuclear factor-B (RANK) expressed by osteoclasts. This interaction results in osteoclast differentiation and activation.[32][33] Additionally, osteoblasts produce osteoprotegerin (OPG), which is a decoy receptor for RANKL. OPG can occupy the RANK-binding site, thereby inhibiting activation of osteoclast precursor cells.[33]
With the continued migration of osteoblasts and osteoclasts, the hard callus undergoes repeated remodeling, termed 'coupled remodeling.' This 'coupled remodeling' is a balance of resorption by osteoclasts and new bone formation by osteoblasts. The center of the callus is ultimately replaced by compact bone, while the callus edges become replaced by lamellar bone. Substantial remodeling of the vasculature occurs alongside these changes. The process of bone remodeling lasts for many months, ultimately resulting in the regeneration of the normal bone structure.[15][34][35][36]
The newly formed bone (woven bone) is remodeled via organized osteoblastic-osteoclastic activity and further shaped in response to mechanical stress (Wolff's law) and electric charges (piezoelectric charges); the compression side is electronegative and stimulates bone formation, and the tension side is electropositive and stimulates osteoclasts. An important point to expand on is endochondral ossification, the process by which cartilage is converted to bone. As described above, this occurs during the formation of a bony callus, in which the newly formed collagen-rich cartilaginous callus gets replaced by immature bone.
This process is also the key to forming long bones in the fetus, in which the bony skeleton replaces the hyaline cartilage model. The second type of ossification also occurs in the fetus: intramembranous ossification, the process by which mesenchymal tissue (primitive connective tissue) is converted directly into bone, with no cartilage intermediate. This process takes place in the flat bones of the skull.[37]
Clinical Significance
Aspiration for ideal fracture healing necessitates a comprehensive understanding of all factors that directly or indirectly influence the healing process. The main pillars of fracture healing are a good biological environment with adequate blood supply and a good mechanical environment with adequate stability. The Arbeitsgemeinschaft für Osteosynthesefragen (AO) Foundation has established 4 principles for ideal fracture healing. This includes fracture reduction to restore anatomy, fracture fixation to achieve absolute or relative stability, preservation of the blood supply to the bone and surrounding soft tissues, and early, safe mobilization. The list of factors that affect fracture healing is exhaustive; however, it can be broadly categorized into local and systemic factors.[38]
Local Factors
- The blood supply and the biological environment are the most important local factors affecting fracture healing. Immediately after the fracture, the surrounding blood vessels are disrupted, resulting in reduced blood supply. This improves over the next few hours to days after the fracture, reaches its peak at 2 weeks, then declines back to normal between 3 and 5 months. Reduced blood supply to the fracture site can lead to delayed union or non-union. Bone blood supply should also be considered in the operative treatment of fractures and the prosthesis used. For example, reaming for intramedullary nailing would compromise 50% to 80% of the endosteal circulation. Also, canal-tight-fitting nails compromise the endosteal blood supply compared with looser-fitting nails, which allow better endosteal reperfusion.
- Fracture Characteristics and the mechanical environment: Excessive movement and malalignment. Extensive soft-tissue damage and soft tissue caught within the fracture site can lead to delayed union or non-union, as well as increased bone comminution and loss. Additionally, specific fracture patterns are more likely to develop non-union or delayed union, such as segmental fractures or fractures with butterfly fragments.
- Infection can significantly compromise the healing process, leading to non-union or delayed union.
Systemic Factors
- Advanced age: the elderly have a lower capacity for fracture healing than the younger population. Aging influences the inflammatory response during fracture healing. With aging, the immune response weakens, and a systemic pro-inflammatory state increases.[39]
- Obesity: In animal studies, lower levels of FGF and TGF-β and higher levels of TNF-α were reported more frequently in obese mice and contributed to delayed fracture healing.[40]
- Anemia
- Endocrine conditions: diabetes mellitus affects the fracture healing process in multiple ways; the fracture callus has low cellular content, resulting in a weak callus. Endochondral ossification is delayed, and fracture healing is generally prolonged compared to the general population. Menopause and parathyroid problems also compromise the fracture-healing process.
- Steroid administration.[41]
- Malnutrition: A high proportion of patients who developed delayed union or non-union were reported to have metabolic compromise, especially vitamin D deficiency. Calcium deficiency is another factor compromising bone union. Calcium deficiency can be secondary to gastrointestinal malabsorption or endocrine problems such as secondary hyperparathyroidism.[42]
- Smoking: Nicotine inhibits angiogenesis and forms weak calluses with an overall delay in the fracture healing process.
- Medications: Certain medications can directly or indirectly affect fracture healing. NSAIDs can result in delayed union due to COX enzyme inhibition. For example, systemic corticosteroids have been reported to increase the rate of nonunion in intertrochanteric femur fractures. Conversely, long-term use of bisphosphonates has been associated with osteoporotic fractures such as subtrochanteric femoral insufficiency fractures. Quinolones have been reported to be toxic to chondrocytes, with the consequent compromise of the fracture healing process.[43][44]
Fractures have significant mortality and morbidity; an interprofessional approach is essential for good outcomes.[45][46][47] There are multiple methods that the interprofessional team can utilize to promote/stimulate fracture healing, including:
- Dietary supplements such as calcium, protein, vitamins C and D.
- Bone stimulators, which can be electrical, electromagnetic, or ultrasound. The current effectiveness of these methods is still equivocal, and this area requires further research. There are 4 principal modes of electrical stimulation; the direct current reduces osteoclast activity and increases osteoblast activity by creating an alkaline tissue environment and reducing oxygen concentration. In contrast, the alternating current affects collagen synthesis and cartilage calcification. The other 2 types are magnetic, either pulsed electromagnetic fields that result in the calcification of fibrocartilage or combined magnetic fields that increase the concentrations of transforming growth factor beta and bone morphogenic proteins.[48] Ultrasound, such as LIPUS (low-intensity pulsed ultrasound has been reported to augment fracture healing and increase the strength of the formed callus, with healing rates in non-union and delayed unions approaching 80%. LIPUS improves fracture healing by increasing chondrocytes, soft callus formation, and, consequently, earlier endochondral ossification.[49][50]
- A bone graft involves using bone to help provide a scaffold for the newly forming bone. This graft can be from the patient's body (autograft) or a deceased donor (allograft).[48][51]
Nursing, Allied Health, and Interprofessional Team Interventions
Fracture healing is regulated by the type and extent of the fracture, the stability of the fracture's fixation, and biological processes, including those associated with skeletal ontogeny.[1] The interprofessional team needs to follow up with the patient regularly throughout the healing process to ensure proper healing and maintain fixation stability. In some instances, physical therapy be necessary, and the physical therapist must communicate back the patient's progress, along with any possible concerns, to the team. As mentioned above, counsel to eat a nutritious diet and refrain from smoking and drinking alcohol are crucial factors in enhancing fracture healing. The interprofessional approach with open communication between all team members help drive optimal fracture healing.
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