Extract
Fracture-healing is a complex, highly organized biological process that leads to the restoration of skeletal integrity by the regeneration of bone. This unique property differentiates bone from other tissues and is essential for skeletal health, homeostasis, and survival. Although fracture-healing is one of the most consistent and reliable reparative responses of human tissue, its impairment or failure can lead to devastating clinical consequences. Conversely, a comprehensive understanding of the basic science of fracture-healing may reveal some of the most well-kept secrets of nature, providing clinicians and scientists with new paths for investigation and leading to advanced therapies for the treatment of skeletal injuries and diseases. This article summarizes the key discussion points of the 2007 American Academy of Orthopaedic Surgeons (AAOS) Research Symposium entitled "Fracture Repair: Challenges and Opportunities." The major goals of this meeting were (1) to identify the unmet needs and research directions for basic, translational, and clinical research in fracture-healing so as to guide the scientific community, and (2) to provide critical feedback to the National Institutes of Health (NIH) to impact their long-range planning and priority-setting processes.
Fracture-healing is a complex, highly organized biological process that leads to the restoration of skeletal integrity by the regeneration of bone. This unique property differentiates bone from other tissues and is essential for skeletal health, homeostasis, and survival. Although fracture-healing is one of the most consistent and reliable reparative responses of human tissue, its impairment or failure can lead to devastating clinical consequences. Conversely, a comprehensive understanding of the basic science of fracture-healing may reveal some of the most well-kept secrets of nature, providing clinicians and scientists with new paths for investigation and leading to advanced therapies for the treatment of skeletal injuries and diseases. This article summarizes the key discussion points of the 2007 American Academy of Orthopaedic Surgeons (AAOS) Research Symposium entitled "Fracture Repair: Challenges and Opportunities." The major goals of this meeting were (1) to identify the unmet needs and research directions for basic, translational, and clinical research in fracture-healing so as to guide the scientific community, and (2) to provide critical feedback to the National Institutes of Health (NIH) to impact their long-range planning and priority-setting processes.
The symposium was organized in a "bench-to-bedside" manner, beginning with presentations on basic- science concepts and followed by discussions on translational research, emerging technologies, and the design and conduct of clinical investigations. The supplement to this issue of The Journal carries full-length manuscripts for these presentations. However, in order to identify the challenges, opportunities, and directions for future research, breakout sessions on tissue responses and cellular recruitment after skeletal injury, cellular signaling, translational research, and clinical trial design provided the setting for meeting these objectives. The output from those sessions forms the basis of this report.
Our current understanding of the early events of fracture-healing recognizes that several cell types, including those resident at the site of the injury as well as others that are recruited in response to chemotactic factors, participate in this process. Some cells are already committed to a chondrogenic or osteogenic pathway, while others are pluripotential mesenchymal cells. These undifferentiated cells appear to be derived from multiple lineages, and they may be present in the microenvironment of the fracture or may migrate to the fracture site from an unknown distance. It is presumed that these cells are recruited from the external soft tissues and bone marrow. However, on the basis of these beliefs and assumptions, it is evident that clear knowledge is lacking regarding the following questions: Where do the cells that initiate the regeneration of bone as a part of this repair process come from? Do cells from these divergent sources differ in the nature of their contribution to the repair process? How do the cells choose their fate, and how are they directed to differentiate into chondroblasts or osteoblasts as opposed to fibroblasts, adipocytes, myoblasts, or other cells in the mesengenic lineage? Can cells be recruited to the fracture site from remote locations such as hematopoietic organs? Indeed, recent reports have suggested that osteoblast progenitors circulate in the peripheral blood and home in to sites of fracture repair1-3.
The ability to answer some of these questions may involve the development of new experimental models to trace cell lineage; to determine the signaling interplay between chondrogenic, osteogenic, angiogenic, and other types of factors; and to identify pathways that may be shared among several morphogens such as those in the transforming growth factor-beta and Wnt superfamilies. Moreover, just as our understanding of human gestational development requires answers to questions such as "How do stem cells differentiate into certain tissues, and what positional cues tell cells to form upper or lower extremities?", it is critical to understand how signals following an injury seem to promote inflammation but also recruit and instruct cells to regenerate bone as opposed to form scar. The potential roles of the mechanical strain environment and the extracellular matrix in stimulating cell growth, proliferation, and differentiation are also unknown.
Once cells are recruited to the fracture site, and as they attach, proliferate, and begin to express their phenotype, intracellular and extracellular signaling coordinates the repair and regeneration processes. These signaling events may include growth factor, chemical, electrical, and mechanical pathways. More scientific progress has been made in understanding intracellular signal transduction as opposed to regulation of growth factor availability in the extracellular space, but a research focus in both settings is needed to advance our understanding of skeletal repair.
Once a cell receives a stimulus, an intracellular signaling cascade is triggered. Different types of stimuli may be perceived differently by the cell and thus trigger different intracellular responses. However, pathways may converge on each other intracellularly, allowing divergent growth factors to yield similar responses. One important area of research is to establish the overlaps, redundancies, synergies, and possibilities for alternative signaling pathways in cells. How cells integrate signals from multiple sources and how these signals initiate fracture-healing responses are not well understood. Another area that merits much greater understanding is the potential role of the cell cycle in determining the cell's ability to respond to an external stimulus or to mitigate its effects through intracellular pathways. Answers to these and other questions will form the basis for understanding clinically relevant concepts such as the effects of age or gender on fracture-healing.
Far less is understood about how ligands move through the extracellular space between cells. Many questions remain unanswered: What are the spatial and temporal characteristics and conditions that affect a signaling factor's ability to reach responsive cells and allow them to participate in fracture repair? Which signaling factors are associated with the local cellular niche and which arise from systemic sources? At present, the ability to document the spatial and temporal attributes of regulatory factors is limited because of the lack of technology to track or monitor the multiple regulators of cellular responses and responsiveness. As a result, there is an opportunity to consider the development of biosensors or imaging strategies to enable quantification and measurement of these factors in time and space. A deeper understanding of the mechanisms of cell-to-cell contact and communication is needed. The potential role of the extracellular matrix in regulating cell morphology, and the way changes in cell shape affect cell function and differentiation potential with regard to fracture-healing, could yield important information to advance our knowledge in this field.
As part of the wounding associated with fracture, trauma occurs not only to bone but also to muscle, nerves, vascular components, and other tissues. The responses of these tissues, which likely interact with those from progenitor cells in the mesengenic lineage, must influence the fracture-healing process. There is a great need to understand the neurotrophic and myotrophic influences (chemical, electrical, and mechanical) on skeletal repair and how local environmental factors impact the activities of cells. An understanding of these concepts is required before it will be possible to fully understand the roles of factors that may perturb fracture-healing, such as local blood supply, systemic health, and infection.
New scientific approaches may be needed to understand how cells integrate a large number of spatially and temporally distinct signals from a variety of extracellular sources. The key to discovering these mechanisms may depend on new scientific approaches that provide a means to characterize the interdependent, conditional, interactive, and modifying effects of the different regulatory signals. Applying the discipline of complex systems analysis or using approaches that utilize computational models and/or bioinformatics algorithms may provide a more comprehensive approach to answering these questions.
Advanced knowledge of the cellular biology of bone repair and regeneration could form the basis for investigations into new strategies to improve the healing of fractures. An understanding of the potential role of genetic variance on fracture-healing or the response of a patient to a specific intervention is very much needed. To address these questions, it is necessary to know how well current clinical therapies impact the fracture-repair process and what is already known of the role of morphogens and potentiation factors and their binding to specific molecular targets in the fracture-healing cascade. New natural and synthetic factors that influence bone repair need to be evaluated in terms of their effects on cell proliferation, differentiation, and ultimately tissue regeneration. Ideally, such studies would involve direct comparison with well-characterized growth factors. It must be recognized that cellular responses to specific factors will differ among cells, and that a factor that has a beneficial effect in one cell type that participates in fracture repair may have a detrimental effect in another. Further elucidation of these concepts is essential to identify methods of translating knowledge of the basic mechanisms of fracture-healing from animal studies to patients.
In order to approach the translational aspects of these research paradigms, better imaging technologies are required to quantitate cells and their responses to environmental and systemic influences. New experimental models that specifically reflect clinical situations may be needed. Importantly, basic scientists need to help clinical scientists translate not only their basic-science knowledge but also their methods used for measurement of healing responses so that clinical investigators can determine how to identify measurable end points in clinical research scenarios. For example, most basic-science studies of fracture-healing utilize biomechanical testing and advanced methods of histology and histomorphometry to measure healing. The inability to load a healed human fracture to failure, or to sample it for histological analysis, requires that innovative thought be applied to identify and validate quantitative methods that will be as reliable in the clinic as those methods employed in the laboratory.
The development and selection of appropriate animal models for translating basic-science concepts into clinical therapies is a major challenge and an essential step in bringing new technologies to the bedside. Investigators must develop models that are relevant to specific types of fractures, to fractures that occur in specific populations, or to those that occur as a result of pathological conditions (e.g., osteoporosis, diabetes, osteogenesis imperfecta, and immune deficiency conditions). This can be very challenging, as some of the most frequently encountered clinical conditions may not have been effectively modeled.
A clearer understanding of the types of questions that should be answered with small-animal models or large-animal models must be established. Certain concepts in fracture-healing can be elucidated by manipulation of the animal's genome (e.g., knockout models, use of interfering RNAs, and gain-of-function and loss-of-function systems), while others require large animals whose anatomical structure more appropriately mimics a clinical setting. For example, questions relating to the fundamental mechanisms of cellular and tissue responses may be answered with small animals, while those investigating the effects of fixation devices or other types of implants may require larger animals. In certain cases, it may be not only the size of the animal but also its phylogenetic relationship to humans that determines the most appropriate model. In certain settings, the use of primates may be required to establish the efficacy of a new drug, implant, or other type of intervention. Indeed, there is a need to determine the ability to perform certain types of experiments without the use of animals but rather with the use of computational models.
New technologies to be translated into better ways of treating fractures include the development of better delivery vehicles for morphogens and cells, the use of cells with scaffolds to provide appropriate composite constructs, and the development of systemic strategies for enhancing the normal process of fracture-healing. The identification of methods to locally or systemically optimize the fracture-healing environment could greatly advance fracture care. Systematic exploration of resorbable polymers and other bioresorbable delivery vehicles that can be tailored for the delivery of specific interventions is needed. It is necessary to determine whether some bioactive factors need to be delivered in a controlled-release fashion, whether single factors are sufficient to stimulate healing, or whether certain factors need to be replaced with so-called "cocktails" of multiple morphogens. Investigators must also be mindful of the costs associated with these technologies; evolution from the development of expensive recombinant proteins to the use of small synthetic molecules may be worthy of consideration. As technologies to address these and other questions become more sophisticated, scientists must carefully determine their impact on safety, and experiments to elucidate issues of safety must occupy a more prominent place in the research agenda.
Studies to develop methods for monitoring the fracture-healing process will be extremely important as new technologies for intervention are introduced in the clinic. The determination of ways to better understand how certain patient factors or behavior patterns cause delays in fracture-healing, the identification of biomarkers that predict healthy or unhealthy fracture-healing responses, and the development of surrogate markers for fracture-healing could greatly advance this field of research.
Over the past fifty years, orthopaedic trauma care and fracture management have advanced substantially. New knowledge of the biology and biomechanics of the musculoskeletal system, the development of novel implants and fixation devices, and improvements in wound management have greatly impacted our ability to care for skeletal injuries. However, with the era of molecular medicine and advanced biomedical engineering on us, clinical research, outcomes research, and investigations into the use of cost-effective strategies for improving fracture care will be the focus of attention in the future. Developing a better understanding of the patient with a fracture and determining what information is required in order to plan treatment and predict outcomes will be essential for translating basic-science technologies into clinically effective treatments.
To achieve these goals, answers to the following questions are needed: What are the comorbid medical conditions (e.g., diabetes, obesity, older age, smoking, and infection) and physical factors that interfere with fracture-healing? What therapeutic modalities interfere with fracture-healing (e.g., nonsteroidal anti-inflammatory drugs, chemotherapy, and radiation therapy) and what strategies are in place or are under investigation to determine how to overcome their inhibitory effects? Why do certain fractures in certain bones heal more predictably than others? What drives these differences? Are they simply related to blood supply, or do local hormonal or cellular mechanisms play a role in determining healing capacity? Fracture-healing is generally not a problem, for example, when it occurs in the diaphysis of the femur; why does the tibia have more difficulties? Is it really possible to accelerate the healing of normal fractures? What means (local and/or systemic) can be used to accomplish this, and by how much can we expect to be able to accelerate healing under normal conditions? What are the most effective synergies of cells, molecules, scaffolds, and physical forces that can enhance fracture-healing? How do we identify these combinations most cost-effectively? How will it be possible to incorporate these concepts into clinical care, paying attention to safety, efficacy, and required duration of treatment? When clinical trials are designed, what is the potential impact of socioeconomic, racial, ethnic, and psychological factors on stratifying patients with regard to treatment?
To address many of these questions, additional sources of information are needed. It is important to determine the prevalence and the demographics of the fractures that show delayed or failed healing and how their occurrence presents a burden to society. It is also important to identify the most appropriate primary and secondary end points when clinical trials are designed and to determine the relationship between quantifiable aspects of fracture-healing and important patient outcomes such as function and quality of life. Clinicians and scientists must do a better job of determining when a fracture is healed or predicting how it will heal by noninvasive methods of assessment. Moreover, while current classification systems for fractures may be appropriate to allow surgeons to communicate with each other and plan operative interventions, these systems may not be the best ways of classifying fractures for the purposes of clinical trials. Clinicians and scientists must work with commercial entities and governing bodies to address the regulatory issues inherent in the development and application of new technologies.
One of the most consistently overlooked aspects of fracture-healing research has been the role of psychological issues and the impact of psychiatric disease. Traditional orthopaedic measurements do not take into account the effects of psychological distress, despite the fact that posttraumatic stress disorders, depression, and the use of antidepressive and antipsychotic drugs are common among patients with fractures4,5. Indeed, in one animal model, experimental frustration induced in mice negatively impacted wound-healing6.
Further research is needed on developing patient-specific outcomes of fracture-healing interventions. What instruments and tools are needed in order to measure the effectiveness of an intervention on improving a patient's outcome? Can we make effective treatments more cost-effective and accessible? How can clinical investigators, health-services researchers, and health-care providers make more effective connections between patient-oriented outcomes and clinically relevant end points?
As basic, translational, and clinical research becomes more sophisticated, funding of investigations and financial support to develop new technologies will become more challenging. More premarket analyses and postmarket surveillance efforts need to be introduced to demonstrate efficacy or unpredicted or unintended effects of therapeutic approaches. Registries should be developed to longitudinally incorporate comprehensive health-care information concerning populations at risk for abnormal fracture-healing and to develop better profiles for future clinical trials. Among the greatest challenges in performing clinical research is choosing the right question and identifying clinically relevant and quantifiable end points. Frequently, clinicians and scientists identify a problem but do not formulate a question that is posed in the form of a testable hypothesis. Similarly, testable hypotheses may be proposed, but the means by which to test them and quantitatively measure responses and outcomes are difficult. A concerted effort must be made to initiate studies that can provide information relevant to the medical and surgical communities as well as meet regulatory requirements. Studies must ensure that the end points relate directly to the hypothesis as well as to clinical practice, regardless of whether those findings are positive or negative. Indeed, scientists should be encouraged to more consistently publish their negative results. This will be increasingly important in an era when expensive technologies are investigated or when biological agents are only shown to have effects when they are used at supraphysiological doses.
Several other issues were discussed at the AAOS-NIH Symposium, and these addressed some of the more vexing challenges in fracture-healing research. First, it is necessary to attract, train, and support new clinician-scientists who have interests and skills in basic-science research, clinical research, and outcomes research pertaining to fracture-healing. Conversely, mechanisms to educate basic scientists about pressing clinical problems, and mechanisms that foster more effective collaborations between basic scientists and surgeons, are vital. Improvement in the process required to investigate key questions is also essential. It is important to streamline the administrative process and to facilitate and disencumber both new and experienced investigators. Institutional review boards, institutional animal care and use committees, and other review bodies must find ways of accomplishing their tasks without introducing bureaucratic roadblocks or inefficient practices. Determining ways of studying specific types of fractures that occur with less frequency than others is needed in order to conduct statistically well-powered clinical trials. Methods and opportunities for conducting multinational trials and trials that incorporate large numbers of centers, each contributing small numbers of patients, is a difficult but worthwhile goal to pursue. The use of additional tools such as meta-analyses and an understanding of how to conduct a good retrospective case series could be very effective in advancing our knowledge when certain questions do not easily lend themselves to randomized controlled trials.
A supplement that accompanies this issue of The Journal carries some of the most up-to-date, original, and provocative research on topics related to fracture-healing. It is our hope that these initial investigations, and the discussions and interactions stimulated among participants at the symposium, will improve our scientific knowledge and ultimately lead to better care for patients with fractures. The active participation by all symposium participants and the efforts of the chairs of the breakout sessions (see Appendix) made it possible for us to compose this summary and to fulfill our stated goals of identifying unmet needs and opportunities and providing feedback to those who set funding priorities at NIH.
Just three months before this symposium was held, the National Institute of Arthritis and Musculoskeletal and Skin Diseases convened a roundtable session in Bethesda, Maryland, to provide important input to their long-range planning and priority-setting processes on musculoskeletal injury and trauma. The summary of that roundtable session is available through their web site7. We encourage you to read that brief summary and consider its content in conjunction with this article.
On behalf of the AAOS, the National Institute of Arthritis and Musculoskeletal and Skin Diseases of NIH, and symposium participants, we thank The Journal for providing the means to bring this information to its readership and the scientific community at large.
A table listing all symposium participants is available with the electronic versions of this article, on our web site at (go to the article citation and click on "Supplementary Material") and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).
Notes: The authors thank Christy Gilmour and Erin Ransford for their organization of the symposium and their efforts in support of the accompanying supplement.
Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Engl J Med.2005;352:1959-66.3521959
2005
[PubMed][CrossRef]
Shirley D, Marsh D, Jordan G, McQuaid S, Li G. Systemic recruitment of osteoblastic cells in fracture healing. J Orthop Res.2005;23:1013-21.231013
2005
[CrossRef]
Devine MJ, Mierisch CM, Jang E, Anderson PC, Balian G. Transplanted bone marrow cells localize to fracture callus in a mouse model. J Orthop Res.2002;20:1232-9.201232
2002
[CrossRef]
Read KM, Kufera JA, Dischinger PC, Kerns TJ, Ho SM, Burgess AR, Burch CA. Life-altering outcomes after lower extremity injury sustained in motor vehicle crashes. J Trauma.2004;57:815-23.57815
2004
[CrossRef]
Starr AJ, Smith WR, Frawley WH, Borer DS, Morgan SJ, Reinert CM, Mendoza-Welch M. Symptoms of posttraumatic stress disorder after orthopaedic trauma. J Bone Joint Surg Am.2004;86:1115-21.861115
2004
[CrossRef]
Viswanathan K, Dhabhar FS. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proc Acad Natl Sci U S A.2005;102:5808-13.1025808
2005
[CrossRef]