Stem cell-derived exosomes in bone healing: focusing on their role in angiogenesis

Fractures in bone, a tissue critical in protecting other organs, affect patients’ quality of life and have a heavy economic burden on societies. Based on regenerative medicine and bone tissue engineering approaches, stem cells have become a promising and attractive strategy for repairing bone fractures via differentiation into bone-forming cells and production of favorable mediators. Recent evidence suggests that stem cell-derived exosomes could mediate the therapeutic effects of their counterpart cells and provide a cell-free therapeutic strategy in bone repair. Since bone is a highly vascularized tissue, coupling angiogenesis and osteogenesis is critical in bone fracture healing; thus, developing therapeutic strategies to promote angiogenesis will facilitate bone regeneration and healing. To this end, stem cell-derived exosomes with angiogenic potency have been developed to improve fracture healing. This review summarizes the effects of stem cell-derived exosomes on the repair of bone tissue, focusing on the angiogenesis process.     

CD133: Enhancement of Bone Healing by Local Transplantation of Peripheral Blood Cells in a Biologically Delayed Rat Osteotomy Model

Sufficient angiogenesis is crucial during tissue regeneration and therefore also pivotal in bone defect healing. Recently, peripheral blood derived progenitor cells have been identified to have in addition to their angiogenic potential also osteogenic characteristics, leading to the hypothesis that bone regeneration could be stimulated by local administration of these cells. The aim of this study was to evaluate the angiogenic potential of locally administered progenitor cells to improve bone defect healing. Cells were separated from the peripheral blood of donor animals using the markers CD34 and CD133. Results of the in vitro experiments confirmed high angiogenic potential in the CD133(+) cell group. CD34(+) and CD133(+) cells were tested in an in vivo rat femoral defect model of delayed healing for their positive effect on the healing outcome. An increased callus formation and higher bone mineral density of callus tissue was found after the CD133(+) cell treatment compared to the group treated with CD34(+) cells and the control group without cells. Histological findings confirmed an increase in vessel formation and mineralization at day 42 in the osteotomy gap after CD133(+) cell transplantation. The higher angiogenic potential of CD133(+) cells from the in vitro experients therefore correlates with the in vivo data. This study demonstrates the suitability of angiogenic precursors to further bone healing and gives an indication that peripheral blood is a promising source for progenitor cells circumventing the problems associated with bone marrow extraction.     

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

While it is well established that an adequate blood supply is critical to successful bone regeneration, it remains poorly understood how progenitor cell fate is affected by the altered conditions present in fractures with disrupted vasculature. In this study, computational models were used to explore how angiogenic impairment impacts oxygen availability within a fracture callus and hence regulates mesenchymal stem cell (MSC) differentiation and bone regeneration. Tissue differentiation was predicted using a previously developed algorithm which assumed that MSC fate is governed by oxygen tension and substrate stiffness. This model was updated based on the hypothesis that cell death, chondrocyte hypertrophy and endochondral ossification are regulated by oxygen availability. To test this, the updated model was used to simulate the time course of normal fracture healing, where it successfully predicted the observed quantity and spatial distribution of bone and cartilage at 10 and 20 days post-fracture (dpf). It also predicted the ratio of cartilage which had become hypertrophic at 10 dpf. Following this, three models of fracture healing with increasing levels of angiogenic impairment were developed. Under mild impairment, the model predicted experimentally observed reductions in hypertrophic cartilage at 10 dpf as well as the persistence of cartilage at 20 dpf. Models of more severe impairment predicted apoptosis and the development of fibrous tissue. These results provide insight into how factors specific to an ischemic callus regulate tissue regeneration and provide support for the hypothesis that chondrocyte hypertrophy and endochondral ossification during tissue regeneration are inhibited by low oxygen.     

Recent advances in bone regeneration using adult stem cells

Bone is a highly vascularized tissue reliant on the close spatial and temporal association between bloodvessels and bone cells. Therefore, cells that participate in vasculogenesis and osteogenesis play a pivotal role in bone formation during prenatal and postnatal periods. Nevertheless, spontaneous healing of bone fracture is occasionally impaired due to insufficient blood and cellular supply to the site of injury. In these cases, bone regeneration process is interrupted, which might result in delayed union or even nonunion of the fracture. Nonunion fracture is difficult to treat and have a high financial impact. In the last decade, numerous technological advancements in bone tissue engineering and cell-therapy opened new horizon in the field of bone regeneration. This review starts with presentation of the biological processes involved in bone development, bone remodeling, fracture healing process and the microenvironment at bone healing sites. Then, we discuss the rationale for using adult stem cells and listed the characteristics of the available cells for bone regeneration. The mechanism of action and epigenetic regulations for osteogenic differentiation are also described. Finally, we review the literature for translational and clinical trials that investigated the use of adult stem cells(mesenchymal stem cells, endothelial progenitor cells and CD34+ blood progenitors) for bone regeneration.     

Osteoblast recruitment to sites of bone formation in skeletal development,homeostasis, and regeneration

During endochondral bone development, bone‐forming osteoblasts have to colonize the regions of cartilage that will be replaced by bone. In adulthood, bone remodeling and repair require osteogenic cells to reach the sites that need to be rebuilt, as a prerequisite for skeletal health. A failure of osteoblasts to reach the sites in need of bone formation may contribute to impaired fracture repair. Conversely, stimulation of osteogenic cell recruitment may be a promising osteo‐anabolic strategy to improve bone formation in low bone mass disorders such as osteoporosis and in bone regeneration applications. Yet, still relatively little is known about the cellular and molecular mechanisms controlling osteogenic cell recruitment to sites of bone formation. In vitro, several secreted growth factors have been shown to induce osteogenic cell migration. Recent studies have started to shed light on the role of such chemotactic signals in the regulation of osteoblast recruitment during bone remodeling. Moreover, trafficking of osteogenic cells during endochondral bone development and repair was visualized in vivo by lineage tracing, revealing that the capacity of osteoblast lineage cells to move into new bone centers is largely confined to undifferentiated osteoprogenitors, and coupled to angiogenic invasion of the bone‐modeling cartilage intermediate. It is well known that the presence of blood vessels is absolutely required for bone formation, and that a close spatial and temporal relationship exists between osteogenesis and angiogenesis. Studies using genetically modified mouse models have identified some of the molecular constituents of this osteogenic–angiogenic coupling. This article reviews the current knowledge on the process of osteoblast lineage cell recruitment to sites of active bone formation in skeletal development, remodeling, and repair, considering the role of chemo‐attractants for osteogenic cells and the interplay between osteogenesis and angiogenesis in the control of bone formation. Birth Defects Research (Part C) 99:170–191, 2013. © 2013 Wiley Periodicals, Inc.     

A mathematical framework to study the effects of growth factor influences on fracture healing

During fracture healing, multipotential stem cells differentiate into specialized cells responsible for producing the different tissues involved in the bone regeneration process. This cell differentiation has been shown to be regulated by locally expressed growth factors. The details of their regulatory mechanisms need to be understood. In this work, we present a two-dimensional mathematical model of the bone healing process for moderate fracture gap sizes and fracture stability. The inflammatory and tissue regeneration stages of healing are simulated by modeling mesenchymal cell migration; mesenchymal cell, chondrocyte and osteoblast proliferation and differentiation, and extracellular matrix synthesis and degradation over time. The effects of two generic growth factors on cell differentiation are based on the experimentally studied chondrogenic and osteogenic effects of bone morphogenetic proteins-2 and 4 and transforming growth factor-beta-1, respectively. The model successfully simulates the progression of healing and predicts that the rate of osteogenic growth factor production by osteoblasts and the duration of the initial release of growth factors upon injury are particularly important parameters for complete ossification and successful healing. This temporo-spatial model of fracture healing is the first model to consider the effects of growth factors. It will help us understand the regulatory mechanisms involved in bone regeneration and provides a mathematical framework with which to design experiments and understand pathological conditions.     

Wnt pathway,an essential role in bone regeneration

Fracture repair is a complex regenerative process initiated in response to injury, resulting in optimal restoration of skeletal function. Although histology characteristics at various phases of fracture repair are clear and well established, much remains to be understood about the process of bone healing, particularly at the molecular signaling level. During the past decade, secreted signaling molecules of the Wnt family have been widely investigated and found to play a central role in controlling embryonic development processes. Wnt signaling pathway also plays a pivotal role in the regulation of bone mass. Recent published data reveal that Wnt signaling pathway is activated during postnatal bone regenerative events, such as ectopic endochondral bone formation and fracture repair. Dysregulation of this pathway greatly inhibits bone formation and healing process. Interestingly, activation of Wnt pathway has potential to improve bone healing, but only utilized after mesenchymal cells have become committed to the osteoblast lineage. These advances suggest an essential role of Wnt pathway in bone regeneration. J. Cell. Biochem. 106: 353–362, 2009. © 2009 Wiley‐Liss, Inc.     

Local administration of allogeneic or autologous bone marrow-derived mesenchymal stromal cells enhances bone formation similarly in distraction osteogenesis

Background aimsDistraction osteogenesis (DO) is a surgical technique to promote bone regeneration that requires a long time for bone healing. Bone marrow-derived mesenchymal stromal cells (MSCs) have been applied to accelerate bone formation in DO. Allogeneic MSCs are attractive, as they could be ready to use in clinics. Whether allogeneic MSCs would have an effect similar to autologous MSCs with regard to promoting bone formation in DO is still unknown. This study compares the effect of autologous MSCs versus allogeneic MSCs on bone formation in a rat DO model.MethodsRat bone marrow-derived MSCs were isolated, characterized and expanded in vitro. Adult rats were subjected to right tibia transverse osteotomy. On the third day of distraction, each rat received one injection of phosphate-buffered saline (PBS), autologous MSCs or allogeneic MSCs at the distraction site. Tibiae were harvested after 28 days of consolidation for micro-computed tomography examination, mechanical test and histological analysis.ResultsResults showed that treatment with both allogeneic and autologous MSCs promoted bone formation, with significantly higher bone mass, mechanical properties and mineral apposition rate as well as expression of angiogenic and bone formation markers at the regeneration sites compared with the PBS-treated group. No statistical difference in bone formation was found between the allogeneic and autologous MSC treatment groups.ConclusionsThis study indicates that allogeneic and autologous MSCs have a similar effect on promoting bone consolidation in DO. MSCs from an allogeneic source could be used off-the-shelf with DO to achieve early bone healing.     

Longitudinal Analysis of Osteogenic and Angiogenic Signaling Factors in Healing Models Mimicking Atrophic and Hypertrophic Non-Unions in Rats

Impaired bone healing can have devastating consequences for the patient. Clinically relevant animal models are necessary to understand the pathology of impaired bone healing. In this study, two impaired healing models, a hypertrophic and an atrophic non-union, were compared to physiological bone healing in rats. The aim was to provide detailed information about differences in gene expression, vascularization and histology during the healing process. The change from a closed fracture (healing control group) to an open osteotomy (hypertrophy group) led to prolonged healing with reduced mineralized bridging after 42 days. RT-PCR data revealed higher gene expression of most tested osteogenic and angiogenic factors in the hypertrophy group at day 14. After 42 days a significant reduction of gene expression was seen for Bmp4 and Bambi in this group. The inhibition of angiogenesis by Fumagillin (atrophy group) decreased the formation of new blood vessels and led to a non-healing situation with diminished chondrogenesis. RT-PCR results showed an attempt towards overcoming the early perturbance by significant up regulation of the angiogenic regulators Vegfa, Angiopoietin 2 and Fgf1 at day 7 and a further continuous increase of Fgf1, -2 and Angiopoietin 2 over time. However µCT angiograms showed incomplete recovery after 42 days. Furthermore, lower expression values were detected for the Bmps at day 14 and 21. The Bmp antagonists Dan and Twsg1 tended to be higher expressed in the atrophy group at day 42. In conclusion, the investigated animal models are suitable models to mimic human fracture healing complications and can be used for longitudinal studies. Analyzing osteogenic and angiogenic signaling patterns, clear changes in expression were identified between these three healing models, revealing the importance of a coordinated interplay of different factors to allow successful bone healing.     

New insights on the reparative cells in bone regeneration and repair

Bone possesses a remarkable repair capacity to regenerate completely without scar tissue formation. This unique characteristic, expressed during bone development, maintenance and injury (fracture) healing, is performed by the reparative cells including skeletal stem cells (SSCs) and their descendants. However, the identity and functional roles of SSCs remain controversial due to technological difficulties and the heterogeneity and plasticity of SSCs. Moreover, for many years, there has been a biased view that bone marrow is the main cell source for bone repair. Together, these limitations have greatly hampered our understanding of these important cell populations and their potential applications in the treatment of fractures and skeletal diseases. Here, we reanalyse and summarize current understanding of the reparative cells in bone regeneration and repair and outline recent progress in this area, with a particular emphasis on the temporal and spatial process of fracture healing, the sources of reparative cells, an updated definition of SSCs, and markers of skeletal stem/progenitor cells contributing to the repair of craniofacial and long bones, as well as the debate between SSCs and pericytes. Finally, we also discuss the existing problems, emerging novel technologies and future research directions in this field.     

Differential distribution of V-type H+-ATPase and Na+/K+-ATPase in the branchial chamber of the palaemonid shrimp Macrobrachium amazonicum

Increased fragility fracture risk with improper healing is a frequent and severe complication of insulin resistance (IR). The mechanisms impairing bone health in IR are still not fully appreciated, which gives importance to studies on bone pathologies in animal models of diabetes. Mice deficient in leptin signaling are widely used models of IR and its comorbidities. Leptin was first recognized as a hormone, regulating appetite and energy balance; however, recent studies have expanded its role showing that leptin is a link between insulin-dependent metabolism and bone homeostasis. In the light of these findings, it is intriguing to consider the role of leptin resistance in bone regeneration. In this study, we show that obese diabetic mice lacking leptin receptor (db/db) are deficient in postnatal regenerative osteogenesis. We apply an ectopic osteogenesis and a fracture healing model, both showing that db/db mice display compromised bone acquisition and regeneration capacity. The underlying mechanisms include delayed periosteal mesenchymatic osteogenesis, premature apoptosis of the cartilage callus and impaired microvascular invasion of the healing tissue. Our study supports the use of the db/db mouse as a model of IR associated bone-healing deficits and can aid further studies of mesenchymatic cell homing and differentiation, microvascular invasion, cartilage to bone transition and callus remodeling in diabetic fracture healing.     

Metalloproteinases and their inhibitors in angiogenesis

Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is an integral part of physiological processes such as embryonic development, the female reproductive cycle and wound healing. Angiogenesis is also central to a variety of pathologies including cancer, where it is recognised as being crucial for the growth of solid tumours. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, most notably MMP-2 and -9 and membrane-type-1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, liberation of angiogenic factors, production of endogenous angiogenic inhibitors, and the unmasking of cryptic biologically relevant sites in ECM components. This review brings together what is currently known about the functions of the MMPs and the closely related adamalysin metalloproteinase (ADAM) family in angiogenesis, and discusses how this information might be useful in manipulation of the angiogenic process, with a view to controlling aberrant neovascularisation.     

Regulation of fracture repair by growth factors.

Fractured bones heal by a cascade of cellular events in which mesenchymal cells respond to unknown regulators by proliferating, differentiating, and synthesizing extracellular matrix. Current concepts suggest that growth factors may regulate different steps in this cascade (10). Recent studies suggest regulatory roles for PDGF, aFGF, bFGF, and TGF-beta in the initiation and the development of the fracture callus. Fracture healing begins immediately following injury, when growth factors, including TGF-beta 1 and PDGF, are released into the fracture hematoma by platelets and inflammatory cells. TGF-beta 1 and FGF are synthesized by osteoblasts and chondrocytes throughout the healing process. TGF-beta 1 and PDGF appear to have an influence on the initiation of fracture repair and the formation of cartilage and intramembranous bone in the initiation of callus formation. Acidic FGF is synthesized by chondrocytes, chondrocyte precursors, and macrophages. It appears to stimulate the proliferation of immature chondrocytes or precursors, and indirectly regulates chondrocyte maturation and the expression of the cartilage matrix. Presumably, growth factors in the callus at later times regulate additional steps in repair of the bone after fracture. These studies suggest that growth factors are central regulators of cellular proliferation, differentiation, and extracellular matrix synthesis during fracture repair. Abnormal growth factor expression has been implicated as causing impaired or abnormal healing in other tissues, suggesting that altered growth factor expression also may be responsible for abnormal or delayed fracture repair. As a complete understanding of fracture-healing regulation evolves, we expect new insights into the etiology of abnormal or delayed fracture healing, and possibly new therapies for these difficult clinical problems.     

Fracture healing as a post-natal developmental process: molecular,spatial, and temporal aspects of its regulation

Fracture healing is a specialized post-natal repair process that recapitulates aspects of embryological skeletal development. While many of the molecular mechanisms that control cellular differentiation and growth during embryogenesis recur during fracture healing, these processes take place in a post-natal environment that is unique and distinct from those which exist during embryogenesis. This Prospect Article will highlight a number of central biological processes that are believed to be crucial in the embryonic differentiation and growth of skeletal tissues and review the functional role of these processes during fracture healing. Specific aspects of fracture healing that will be considered in relation to embryological development are: (1) the anatomic structure of the fracture callus as it evolves during healing; (2) the origins of stem cells and morphogenetic signals that facilitate the repair process; (3) the role of the biomechanical environment in controlling cellular differentiation during repair; (4) the role of three key groups of soluble factors, pro-inflammatory cytokines, the TGF-beta superfamily, and angiogenic factors, during repair; and (5) the relationship of the genetic components that control bone mass and remodeling to the mechanisms that control skeletal tissue repair in response to fracture.     

Systemic Inhibition of Canonical Notch Signaling Results in Sustained Callus Inflammation and Alters Multiple Phases of Fracture Healing

The Notch signaling pathway is an important regulator of embryological bone development, and many aspects of development are recapitulated during bone repair. We have previously reported that Notch signaling components are upregulated during bone fracture healing. However, the significance of the Notch pathway in bone regeneration has not been described. Therefore, the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model (Mx1-Cre;dnMAML^f/-) to impair RBPjκ-mediated canonical Notch signaling. The Mx1 promoter was synthetically activated resulting in temporally regulated systemic dnMAML expression just prior to creation of bilateral tibial fractures. This allowed for mice to undergo unaltered embryological and post-natal skeletal development. Results showed that systemic Notch inhibition prolonged expression of inflammatory cytokines and neutrophil cell inflammation, and reduced the proportion of cartilage formation within the callus at 10 days-post-fracture (dpf) Notch inhibition did not affect early bone formation at 10dpf, but significantly altered bone maturation and remodeling at 20dpf. Increased bone volume fraction in dnMAML fractures, which was due to a moderate decrease in callus size with no change in bone mass, coincided with increased trabecular thickness but decreased connectivity density, indicating that patterning of bone was altered. Notch inhibition decreased total osteogenic cell density, which was comprised of more osteocytes rather than osteoblasts. dnMAML also decreased osteoclast density, suggesting that osteoclast activity may also be important for altered fracture healing. It is likely that systemic Notch inhibition had both direct effects within cell types as well as indirect effects initiated by temporally upstream events in the fracture healing cascade. Surprisingly, Notch inhibition did not alter cell proliferation. In conclusion, our results demonstrate that the Notch signaling pathway is required for the proper temporal progression of events required for successful bone fracture healing.     

Dysfunctional stem and progenitor cells impair fracture healing with age

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells(MSCs) are directed to replace the bone tissue, while endothelial progenitor cells(EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species,and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics.Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.     

Mathematical Modeling in Wound Healing,Bone Regeneration and Tissue Engineering

The processes of wound healing and bone regeneration and problems in tissue engineering have been an active area for mathematical modeling in the last decade. Here we review a selection of recent models which aim at deriving strategies for improved healing. In wound healing, the models have particularly focused on the inflammatory response in order to improve the healing of chronic wound. For bone regeneration, the mathematical models have been applied to design optimal and new treatment strategies for normal and specific cases of impaired fracture healing. For the field of tissue engineering, we focus on mathematical models that analyze the interplay between cells and their biochemical cues within the scaffold to ensure optimal nutrient transport and maximal tissue production. Finally, we briefly comment on numerical issues arising from simulations of these mathematical models.     

Dimethyloxaloylglycine Improves Angiogenic Activity of Bone Marrow Stromal Cells in the Tissue-Engineered Bone

One of the big challenges in tissue engineering for treating large bone defects is to promote the angiogenesis of the tissue-engineered bone. Hypoxia inducible factor-1α (HIF-1α) plays an important role in angiogenesis-osteogenesis coupling during bone regeneration, and can activate a broad array of angiogenic factors. Dimethyloxaloylglycine (DMOG) can activate HIF-1α expression in cells at normal oxygen tension. In this study, we explored the effect of DMOG on the angiogenic activity of bone mesenchymal stem cells (BMSCs) in the tissue-engineered bone. The effect of different concentrations of DMOG on HIF-1a expression in BMSCs was detected with western blotting, and the mRNA expression and secretion of related angiogenic factors in DMOG-treated BMSCs were respectively analyzed using qRT-PCR and enzyme linked immunosorbent assay. The tissue-engineered bone constructed with β-tricalcium phosphate (β-TCP) and DMOG-treated BMSCs were implanted into the critical-sized calvarial defects to test the effectiveness of DMOG in improving the angiogenic activity of BMSCs in the tissue-engineered bone. The results showed DMOG significantly enhanced the mRNA expression and secretion of related angiogenic factors in BMSCs by activating the expression of HIF-1α. More newly formed blood vessels were observed in the group treated with β-TCP and DMOG-treated BMSCs than in other groups. And there were also more bone regeneration in the group treated with β-TCP and DMOG-treated BMSCs. Therefore, we believed DMOG could enhance the angiogenic activity of BMSCs by activating the expression of HIF-1α, thereby improve the angiogenesis of the tissue-engineered bone and its bone healing capacity.     

Angiogenic factors in bone local environment

Angiogenesis plays an important role in physiological bone growth and remodeling, as well as in pathological bone disorders such as fracture repair, osteonecrosis, and tumor metastasis to bone. Vascularization is required for bone remodeling along the endosteal surface of trabecular bone or Haversian canals within the cortical bone, as well as the homeostasis of the cartilage-subchondral bone interface. Angiogenic factors, produced by cells from a basic multicellular unit (BMU) within the bone remodeling compartment (BRC) regulate local endothelial cells and pericytes. In this review, we discuss the expression and function of angiogenic factors produced by osteoclasts, osteoblasts and osteocytes in the BMU and in the cartilage-subchondral bone interface. These include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), BMP7, receptor activator of NF-κB ligand (RANKL) and epidermal growth factor (EGF)-like family members. In addition, the expression of EGFL2, EGFL3, EGFL5, EGFL6, EGFL7, EGFL8 and EGFL9 has been recently identified in the bone local environment, giving important clues to their possible roles in angiogenesis. Understanding the role of angiogenic factors in the bone microenvironment may help to develop novel therapeutic targets and diagnostic biomarkers for bone and joint diseases, such as osteoporosis, osteonecrosis, osteoarthritis, and delayed fracture healing.     

Computational simulation of the early stage of bone healing under different configurations of locking compression plates

Flexible fixation or the so-called ‘biological fixation’ has been shown to encourage the formation of fracture callus, leading to better healing outcomes. However, the nature of the relationship between the degree of mechanical stability provided by a flexible fixation and the optimal healing outcomes has not been fully understood. In this study, we have developed a validated quantitative model to predict how cells in fracture callus might respond to change in their mechanical microenvironment due to different configurations of locking compression plate (LCP) in clinical practice, particularly in the early stage of healing. The model predicts that increasing flexibility of the LCP by changing the bone–plate distance (BPD) or the plate working length (WL) could enhance interfragmentary strain in the presence of a relatively large gap size (>3 mm). Furthermore, conventional LCP normally results in asymmetric tissue development during early stage of callus formation, and the increase of BPD or WL is insufficient to alleviate this problem.