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<a href=Injury, Int. J. Care Injured 42 (2011) 549–550 Contents lists available at ScienceDirect Injury journal homepage: www.else vier.com/locate/injury Editorial Fracture healing and bone repair One of the most challenging clinical problems in the trauma speciality is the management of patients with impaired fracture healing and bone defects. The incidence of delayed union and/ or non-union following fractures is thought to be increasing and this has been attributed to the improved survival rates of patients with multiple injuries. This patient population in the past would either succumb at the scene of the accident or shortly after arriving at the local hospital. However, with the advances made in every discipline of medicine more and more of these severely injured patients survive their injuries and consequently they have to undergo prolonged reconstructive procedures for restoration of their associated complex upper and lower extremity injuries. Besides trauma, there are also other conditions in orthopaedic and maxillofacial surgery in which bone regeneration is required such as infection, tumour resection and skeletal abnormalities. Bone regeneration represents a well-orchestrated series of biological events of cellular recruitment, proliferation and differentiation. At the molecular level a large number of mediators and cellular elements facilitate the initiation and evolution of bone repair processes. From the physiological point of view, signalling molecules or growth factors, osteoprogenitor cells, and the extracellular matrix/natural scaffold play a crucial role in creating the foundation for successful bone healing. However, the contribution of the mechanical component cannot be under- estimated and in this respect the recently reported conceptual framework for successful fracture healing, the so-called ‘diamond concept’, attributing equal importance to both the mechanical and biological environment, has provided the clinician with a stepwise approach to deal with complex clinical cases where bone repair is needed. The extent of the mechanical stability that can be achieved at the fracture site is relevant to the type of fixation method that has been selected. Methods of fixation include ORIF (open reduction and internal fixation), external fixation systems, intramedullary nailing systems and more recently, locking plating systems. A spectrum of stability is created with each implant ranging from relative to absolute stability and accordingly promoting the evolution of primary or secondary fracture healing (callous formation). At the site of injury, different cell types including endothelial cells, platelets, macrophages, monocytes and mesenchymal stem cells (MSCs) secrete biologically active molecules. Amongst them, bone morphogenetic proteins (BMPs) (members of the TGF- b superfamily) possess osteoinductive properties thus exerting their effects on undifferentiated cells in the mesenchymal lineage and promoting their proliferation and differentiation to the an osteo- or chondroprogenitor pathway. The extracellular matrix provides the natural scaffold for all the cellular events and interactions. It is considered to be the arena where all of the elements in this cascade of events are evolving and one could argue that it represents the home of the vibrant cell populations. Cell adhesion, migration, proliferation and differentiation are examples of biological processes influenced by the composition and structural organiza- tion of surrounding extracellular matrices. Currently, in the surgeons’ armamentarium, for the treatment of non-unions or bone defects, a number of treatment modalities can be considered either alone or in combination for optimisation of the bone healing process. Typical approaches used in the clinical setting to promote or boost bone regeneration include distraction osteogenesis and bone transport, free fibula vascularised graft, the use of a number of bone grafts (autologous bone, allografts, bone graft substitutes), growth factors, cellular therapies, and other methods such as the induced membrane technique, titanium cages and non-invasive modalities of biophysical stimulation, such as low-intensity pulsed ultrasound (LIPUS) and pulsed electromag- 15,12,16,27,6,28,18,1,21,2,24 these options is variable with inconsistent results in the literature. Recently, systemic administration of pharmacological agents such as parathyroid hormone (PTH) and growth hormone (GH) has gained substantial attention. Preliminary studies have shown promising results but such an approach is still under experimental scrutiny and there are concerns regarding safety issues. Regarding the use of PTH for bone regeneration, there are numerous animal studies and clinical trials demonstrating that intermittent PTH administration induces both cancellous and cortical bone regen- eration, enhances bone mass and increases mechanical bone strength and bone mineral density, with a relatively satisfactory safety profile. Another emerging approach is the application of gene therapy where the transfer of genetic material into targeted cell’s genome allows the expression of bioactive mediators from the cells themselves over a prolonged period of time. Gene transfer can be achieved using a viral (transfection) or a non-viral (transduc- tion) vector, by either an in vivo or ex vivo gene-transfer strategy. Issues of on-going concern with this approach include the cost implications and safety profile. Recently, delivery of growth factors and in particular BMPs using gene therapy for bone regeneration has revealed promising results in animal studies. However, there will be still several years before this method of treatment would be applied routinely in the clinical environment. An emerging multidisciplinary field involving biology, medicine and engineering, the field of ‘tissue engineering’ is expected to 0020–1383/$ – see front matter 2011 Published by Elsevier Ltd. doi: 10.1016/j.injury.2011.03.037 " id="pdf-obj-0-5" src="pdf-obj-0-5.jpg">

Contents lists available at ScienceDirect

Injury

journal homepage: www.else vier.com/locate/injury

<a href=Injury, Int. J. Care Injured 42 (2011) 549–550 Contents lists available at ScienceDirect Injury journal homepage: www.else vier.com/locate/injury Editorial Fracture healing and bone repair One of the most challenging clinical problems in the trauma speciality is the management of patients with impaired fracture healing and bone defects. The incidence of delayed union and/ or non-union following fractures is thought to be increasing and this has been attributed to the improved survival rates of patients with multiple injuries. This patient population in the past would either succumb at the scene of the accident or shortly after arriving at the local hospital. However, with the advances made in every discipline of medicine more and more of these severely injured patients survive their injuries and consequently they have to undergo prolonged reconstructive procedures for restoration of their associated complex upper and lower extremity injuries. Besides trauma, there are also other conditions in orthopaedic and maxillofacial surgery in which bone regeneration is required such as infection, tumour resection and skeletal abnormalities. Bone regeneration represents a well-orchestrated series of biological events of cellular recruitment, proliferation and differentiation. At the molecular level a large number of mediators and cellular elements facilitate the initiation and evolution of bone repair processes. From the physiological point of view, signalling molecules or growth factors, osteoprogenitor cells, and the extracellular matrix/natural scaffold play a crucial role in creating the foundation for successful bone healing. However, the contribution of the mechanical component cannot be under- estimated and in this respect the recently reported conceptual framework for successful fracture healing, the so-called ‘diamond concept’, attributing equal importance to both the mechanical and biological environment, has provided the clinician with a stepwise approach to deal with complex clinical cases where bone repair is needed. The extent of the mechanical stability that can be achieved at the fracture site is relevant to the type of fixation method that has been selected. Methods of fixation include ORIF (open reduction and internal fixation), external fixation systems, intramedullary nailing systems and more recently, locking plating systems. A spectrum of stability is created with each implant ranging from relative to absolute stability and accordingly promoting the evolution of primary or secondary fracture healing (callous formation). At the site of injury, different cell types including endothelial cells, platelets, macrophages, monocytes and mesenchymal stem cells (MSCs) secrete biologically active molecules. Amongst them, bone morphogenetic proteins (BMPs) (members of the TGF- b superfamily) possess osteoinductive properties thus exerting their effects on undifferentiated cells in the mesenchymal lineage and promoting their proliferation and differentiation to the an osteo- or chondroprogenitor pathway. The extracellular matrix provides the natural scaffold for all the cellular events and interactions. It is considered to be the arena where all of the elements in this cascade of events are evolving and one could argue that it represents the home of the vibrant cell populations. Cell adhesion, migration, proliferation and differentiation are examples of biological processes influenced by the composition and structural organiza- tion of surrounding extracellular matrices. Currently, in the surgeons’ armamentarium, for the treatment of non-unions or bone defects, a number of treatment modalities can be considered either alone or in combination for optimisation of the bone healing process. Typical approaches used in the clinical setting to promote or boost bone regeneration include distraction osteogenesis and bone transport, free fibula vascularised graft, the use of a number of bone grafts (autologous bone, allografts, bone graft substitutes), growth factors, cellular therapies, and other methods such as the induced membrane technique, titanium cages and non-invasive modalities of biophysical stimulation, such as low-intensity pulsed ultrasound (LIPUS) and pulsed electromag- 15,12,16,27,6,28,18,1,21,2,24 these options is variable with inconsistent results in the literature. Recently, systemic administration of pharmacological agents such as parathyroid hormone (PTH) and growth hormone (GH) has gained substantial attention. Preliminary studies have shown promising results but such an approach is still under experimental scrutiny and there are concerns regarding safety issues. Regarding the use of PTH for bone regeneration, there are numerous animal studies and clinical trials demonstrating that intermittent PTH administration induces both cancellous and cortical bone regen- eration, enhances bone mass and increases mechanical bone strength and bone mineral density, with a relatively satisfactory safety profile. Another emerging approach is the application of gene therapy where the transfer of genetic material into targeted cell’s genome allows the expression of bioactive mediators from the cells themselves over a prolonged period of time. Gene transfer can be achieved using a viral (transfection) or a non-viral (transduc- tion) vector, by either an in vivo or ex vivo gene-transfer strategy. Issues of on-going concern with this approach include the cost implications and safety profile. Recently, delivery of growth factors and in particular BMPs using gene therapy for bone regeneration has revealed promising results in animal studies. However, there will be still several years before this method of treatment would be applied routinely in the clinical environment. An emerging multidisciplinary field involving biology, medicine and engineering, the field of ‘tissue engineering’ is expected to 0020–1383/$ – see front matter 2011 Published by Elsevier Ltd. doi: 10.1016/j.injury.2011.03.037 " id="pdf-obj-0-15" src="pdf-obj-0-15.jpg">

Editorial

Fracture healing and bone repair

One of the most challenging clinical problems in the trauma speciality is the management of patients with impaired fracture healing and bone defects. 14,8 The incidence of delayed union and/ or non-union following fractures is thought to be increasing and this has been attributed to the improved survival rates of patients with multiple injuries. This patient population in the past would either succumb at the scene of the accident or shortly after arriving at the local hospital. 13,4,7,25,9,22,20,31 However, with the advances made in every discipline of medicine more and more of these severely injured patients survive their injuries and consequently they have to undergo prolonged reconstructive procedures for restoration of their associated complex upper and lower extremity injuries. 11,17,23,26 Besides trauma, there are also other conditions in orthopaedic and maxillofacial surgery in which bone regeneration is required such as infection, tumour resection and skeletal abnormalities. Bone regeneration represents a well-orchestrated series of biological events of cellular recruitment, proliferation and differentiation. At the molecular level a large number of mediators and cellular elements facilitate the initiation and evolution of bone repair processes. From the physiological point of view, signalling molecules or growth factors, osteoprogenitor cells, and the extracellular matrix/natural scaffold play a crucial role in creating the foundation for successful bone healing. However, the contribution of the mechanical component cannot be under- estimated and in this respect the recently reported conceptual framework for successful fracture healing, the so-called ‘diamond concept’, attributing equal importance to both the mechanical and biological environment, has provided the clinician with a stepwise approach to deal with complex clinical cases where bone repair is needed. 10 The extent of the mechanical stability that can be achieved at the fracture site is relevant to the type of fixation method that has been selected. Methods of fixation include ORIF (open reduction and internal fixation), external fixation systems, intramedullary nailing systems and more recently, locking plating systems. A spectrum of stability is created with each implant ranging from relative to absolute stability and accordingly promoting the evolution of primary or secondary fracture healing (callous formation). At the site of injury, different cell types including endothelial cells, platelets, macrophages, monocytes and mesenchymal stem cells (MSCs) secrete biologically active molecules. Amongst them, bone morphogenetic proteins (BMPs) (members of the TGF-b superfamily) possess osteoinductive properties thus exerting their effects on undifferentiated cells in the mesenchymal lineage and promoting their proliferation and differentiation to the an osteo- or

chondroprogenitor pathway. 3 The extracellular matrix provides the natural scaffold for all the cellular events and interactions. It is considered to be the arena where all of the elements in this cascade of events are evolving and one could argue that it represents the home of the vibrant cell populations. Cell adhesion, migration, proliferation and differentiation are examples of biological processes influenced by the composition and structural organiza- tion of surrounding extracellular matrices. 19 Currently, in the surgeons’ armamentarium, for the treatment of non-unions or bone defects, a number of treatment modalities can be considered either alone or in combination for optimisation of the bone healing process. Typical approaches used in the clinical setting to promote or boost bone regeneration include distraction osteogenesis and bone transport, free fibula vascularised graft, the use of a number of bone grafts (autologous bone, allografts, bone graft substitutes), growth factors, cellular therapies, and other methods such as the induced membrane technique, titanium cages and non-invasive modalities of biophysical stimulation, such as low-intensity pulsed ultrasound (LIPUS) and pulsed electromag- netic elds (PEMF). 15,12,16,27,6,28,18,1,21,2,24 The success of each of

these options is variable with inconsistent results in the literature. Recently, systemic administration of pharmacological agents such as parathyroid hormone (PTH) and growth hormone (GH) has gained substantial attention. Preliminary studies have shown promising results but such an approach is still under experimental scrutiny and there are concerns regarding safety issues. Regarding the use of PTH for bone regeneration, there are numerous animal studies and clinical trials demonstrating that intermittent PTH administration induces both cancellous and cortical bone regen- eration, enhances bone mass and increases mechanical bone strength and bone mineral density, with a relatively satisfactory safety profile. 30 Another emerging approach is the application of gene therapy where the transfer of genetic material into targeted cell’s genome allows the expression of bioactive mediators from the cells themselves over a prolonged period of time. 5 Gene transfer can be achieved using a viral (transfection) or a non-viral (transduc- tion) vector, by either an in vivo or ex vivo gene-transfer strategy. Issues of on-going concern with this approach include the cost implications and safety profile. Recently, delivery of growth factors and in particular BMPs using gene therapy for bone regeneration has revealed promising results in animal studies. 29 However, there will be still several years before this method of treatment would be applied routinely in the clinical environment. An emerging multidisciplinary field involving biology, medicine and engineering, the field of ‘tissue engineering’ is expected to

0020–1383/$ – see front matter 2011 Published by Elsevier Ltd.

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Editorial / Injury, Int. J. Care Injured 42 (2011) 549–550

revolutionize the treatment of patients with impaired bone healing. 3 However, the technical issues challenging the tissue engineering approaches are immense. The selection of appropriate cells, scaffold materials, growth factors, and the fluid shear stress and strain from blood flow are parameters that are still under debate. Moreover, the shape of any material designed to be implanted, its porosity, biological behaviour, mechanical proper- ties and resorption profile are of paramount importance. Moreover, incompatibilities between synthetic engineered grafts and host tissues must be quantified and evaluated. Developments in polymeric and ceramic scaffolding systems for cell, protein and gene delivery have seen significant growth. A number of strategies however that have been applied in the clinical setting to enhance bone healing and to restore bone defects have not met expectations. Nonetheless, tissue engineering is expected to continue to provide novel treatment strategies in the years to come. Bone regeneration continues to be an important subject amongst clinicians, researchers and scientists. For this reason, this special issue was compiled to provide the readers with the latest knowledge relevant to this topic. We hope that the information provided in these pages will contribute further to a better understanding of this rapidly expanding field.

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Peter V. Giannoudis* Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds General Infirmary, Clarendon Wing Level A, Great George Street, LS1 3EX Leeds, UK

Elena Jones

Department of Rheumatology, University of Leeds, UK

Thomas A. Einhorn

Department of Orthopaedic Surgery, Boston University

Medical Center, Boston, MA, USA

*Corresponding author. Tel.: +44 0 113 392 2750; fax: +44 0 113 392 3290 E-mail address: pgiannoudi@aol.com (P.V. Giannoudis).