New insights in bone fracture healing

Rezumat:

Aceasta lucrare este o trecere in revista a datelor din literatura de specialitate cu privire la procesul de vindecare al fracturilor osoase. Osul este unul dintre putinele organe care isi mentine potentialul de regenerare in viata adulta, intrucât acesta poseda capacitati considerabile de reparare. Spre deosebire de alte tesuturi care sunt reparate prin formarea unei cicatrice de tesut conjunctiv de slaba calitate, osul este regenerat si cele mai multe dintre proprietatile prefacturii sunt restaurate.

Abordarea ingineriei tisulare standard  ofera solutii pentru vindecarea fracturii, iar restaurarea si regenerarea osoasa includ utilizarea factorilor de crestere a elementelor structurale si a celuleor stem mezenchimale. Desi factorul mecanic este discutat si este considerat un element important in regenerarea osoasa, importanta acestuia este adesea subestimata si nu i se acorda intotdeauna atentia cuvenita. Evidenta stiintifica disponibila sustine conceptul celor patru factori contributori la restaurarea osoasa, carora este necesar sa li se atribuie in egala masura recunoasterea.

Cuvinte-cheie: vindecarea fracturii osoase, restaurarea osoasa, elemente structurare, factori de crestere

Abstract:

This paper is a review of the literature data on bone healing research. Bone is one of the few organs that retains the potential for regeneration in adult life, as it possesses considerable capacities of repair. Unlike other tissues that heal by the formation of a connective tissue scar of poor quality, bone is regenerated and the pre-fracture properties are mostly restored.

The standard tissue engineering approach to provide solutions for impaired fracture healing and bone restoration and regeneration includes the utilisation of growth factors, scaffolds and mesenchymal stem cells. However, although the mechanical environment is discussed and is considered as an important element in bone regeneration, its importance is often underestimated and it is not always given the necessary attention. The available scientific evidence supports the view that all the 4 known factors contributing to bone restoration should be given an equal acknowledgment and recognition.

Keywords: fracture healing, bone restauration, Scaffolds, growth factors

Introduction

Bone is one of the few organs that retains the potential for regeneration in adult life, as it possesses considerable capacities of repair. Unlike other tissues that heal by the formation of a connective tissue scar of poor quality, bone is regenerated and the pre-fracture properties are mostly restored. The expression of this unique characteristic applies either to the periodical remodelling of the human skeleton or to the healing cascade of bone fractures.[1]

With the latest advances made in molecular biology and genetics it is now known that it involves the spatial and temporal coordinated action of several different cell types, proteins and the expression of hundreds of genes working towards restoring its structural integrity without scar formation.

The contemporary consensus and understanding of fracture healing implicates a large numbers of factors at the molecular level in conjunction with physiological and biomechanical principles.[2,3]

The coordinated interaction of these different elements creates the complex pathways of bone healing. Any deficit expressed at any point of the healing cycle alters the physiological sequence of fracture healing and predisposes to complications.

Well-timed and well-aimed interventions are needed to reverse these conditions in order to allow the physiological process of fracture healing to progress to union and thus increase the efficacy of orthopaedic trauma therapies. To achieve this goal the scientific effort has been focused in eliciting the molecular, patho-physiological and biomechanical aspects of bone fracture repair.[4]

The stages of fracture healing reiterate the sequential stages of embryonic endochondral bone formation. Two basic histological types of bone healing are described. Primary healing is rare and refers to a direct attempt of the cells in cortical bone to re-establish the disrupted continuity. It requires absolute contact of the fragments and almost complete stability and minimisation of the inter-fragmentary strains.[5]

Secondary bone healing occurs in the vast majority of bony injuries.Mechanical stability  involves both intramembranous and endochondral ossification and leads to callus formation. Committed osteoprogenitor cells of the periosteum and undifferentiated multipotent mesenchymal stem cells (MSCs) are activated. Callus is a physiological reaction to inter-fragmentary movement and requires the existence of residual cell vitality and adequate blood flow.[6]

In this cascade of events certain biologic prerequisites have been identified. Many local and systemic regulatory factors, cytokines and hormones, as well as extracellular osteoconductive matrix are seen to interact with several cell types. A vibrant cell population is a mandatory first element for an unimpeded bone repair process. Multipotent mesenchymal cells are recruited at the fracture injury site or transferred to it with the blood circulation. Bone marrow response to a fracture includes an early reorganization of the cellular population of the bone marrow to areas of high and low cellular density. The areas of high cellular density are where the MSCs transformation to cells with an osteoblastic phenotype occurs.[7]

Following the identification and quantification of the osteogenic role of bone marrow cells, genetically engineered MSCs and differentiated osteoblasts have been utilized to enhance fracture healing in a number of in vitro and in vivo studies.[8]

The fracture hematoma has been proven to be a source of signalling molecules (interleukins /IL-1, IL-6, tumor necrosis factor-a / TNF-a,fibroblast growth factor / FGF, insulin-like growth factor / IGF, platelet-derived growth factor / PDGF, vascular endothelial growth factor / VEGF,and the TGFbeta superfamily members) that may induce a cascade of cellular events that initiate healing .[9] These factors are secreted by endothelial cells, platelets, macrophages, monocytes, but also by the mesenchymal stem cells, the chondrocytes, the osteocytes and the osteoblasts themselves.[10]

The investigation of the clinical use of these factors has increased dramatically in the last decade. The bone morphogenetic proteins (BMP-2 and BMP-7)represent members of the TGFbeta superfamily that have been studied extensively. They have already passed from the experimental level of testing to the clinical practice and are established methods of biological healing enhancement at areas of delayed fracture healing or nonunions.[11]

A third element of fracture healing is the extracellular matrix that provides the natural scaffold for all the cellular events and interactions. Various osteoconductive materials alone or usually enriched with osteogenic and osteoinductive factors have been used in the clinical practice.

Porous biomaterials such as allograft or xenograft trabecular bone, demineralised bone matrix (DBM)11, collagen, hydroxyapatite, polylactic or polyglycolic acid, bioactive glasses and calciumbased ceramics have been used alone as bone void fillers. They have also been combined with boneactive growth factors in an attempt to acheive a maximal osteogenic effect.[12]

These three biological prerequisites for fracture healing enhancement have gained most of the scientific attention. A triangular-shaped complex of interactions between the potent osteogenic cell populations, the osteoinductive stimulus and the osteoconductive matrix scaffolds are often analysed and extensively studied in the quest for the optimal grafting material. However, a fourth element, which is also mandatory for optimisation of bone fracture repair, should also be taken under consideration and be given the same recognition in terms of significance. Mechanical stability is a crucial factor for bone healing, and is essential for the formation of a callus that bridges the fracture site allowing loads to be transmitted across the fracture line.

The progressive maturation of the fracture callus from woven to lamellar bone depends on this stability. Surgical interventions such as the application of systems of internal or external stabilisation are designed to improve stability of fixation and therby enhance healing. Fracture fixation methods have evolved from the era of ORIF (open reduction and internal fixation) as originally popularised by the AO30, to the contemporary concept of biologic fixation.[13]

Wolff’s law[14] describes the interaction of bone to the applied stresses and its unique characteristic of altering it’s mechanical properties according to them. The application of this law to the clinical setting of fracture healing together with the interplay between parameters as implant rigidity, relative or absolute fracture stability, fracture gap size, and interfragmentary strain are all efforts to express and compute the complex phenomena of bone fracture repair[15]

Relative stability and maximal respect of the soft tissue envelope and the vascularity around the fracture site are considered essential. Scientific research has quantified the essence of relative stability.Splints, casts, intramedullary nails, external fixators and locking plates, after open or mostly closed reduction stabilise the fracture site by minimizing the interfragmentary gap size, and keeping the interfragmentary strain below 10%.[2, 23]

In the clinical setting of fracture fixation in conjunction with bone grafting the mechanical stability necessary for optimal healing has not been adequately studied. The general consensus is that a certain load-shielding period has to be achieved to protect the graft in its initial phase of incorporation.[16]

The role of mechanical stability in the microenvironment of implanted grafts, scaffolds or graft carriers is also essential and sometimes overlooked. These properties vary greatly among the various biomaterials and depend on their macro and micro architecture, as well as porosity[17]

Significant parameters that differentiate the indications of the different scaffolds and biomaterials are the quality and density of the host bone bed and the local biomechanical demands of the fracture site (weight bearing limbor not). Moreover, bone graft biomechanics evolve parallel to the progress of its incorporation and to callus remodelling. All these issues have formed the bases for intense research efforts to improve initial the mechanical properties of the available biomaterials as well as to guarantee the presence of a mechanically reliable construct throughout all the remodelling phase of fracture healing. Recently, 3D porous polymer scaffolds with pore sizes ranging from 150-500 nm have shown optimal results related to their biomechanical properties.[17, 18]

Conclusion

The operative or non-operative techniques of fracture stabilisation, the utilised implants and fixation devices, as well as the mechanical properties of any grafting material all interact and affect the fracture repair process.

The mechanical environment where any graft material is expected to act has equal significance to the biologic properties of the graft itself whether it is the gold standard of autograft or synthetic grafting material.

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Gabriel Ovidiu Dinu

Floreasca Universitary Emergency Hospital