Systemic Mesenchymal Stem Cell Delivery and Axial Mechanical Stimulation Accelerate Fracture Healing

2008 ◽  
Author(s):  
Aaron S. Weaver ◽  
Yu-Ping Su ◽  
Dana L. Begun ◽  
Ralph T. Zade ◽  
Andrea I. Alford ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Repair ◽  
Local Environment ◽  
Cell Types ◽  
Repair Process ◽  
Fracture Site ◽  
Fracture Repair ◽  
Stem Cell Delivery ◽  
Numerous Cell ◽  
Local Cell

Fracture healing is a complex process involving numerous cell types, whose actions are regulated by many factors in their local environment. Mechanical factors are known to exert a strong influence on the actions of these cells and the progression of the repair process. While prior studies have investigated the effect of physical forces on cell differentiation, biofactor expression, and mechanical competence of repair, the mechanosensory and response mechanisms are poorly understood. This study was designed to explore the influence of a controlled mechanical environment on temporal aspects of the bone repair process. Specifically, this study examines how the timing of an applied strain influences local cell behavior during fracture repair, and how this load affects the migration of systemically introduced mesenchymal stem cells (MSCs) to the fracture site.

Effect of Intramedullary Nailing Patterns On Interfragmentary Strain in a Mouse Femur Fracture: a Parametric Finite Element Analysis

2021 ◽  
Author(s):  
Gregory Lowen ◽  
Katherine Garrett ◽  
Moore-Lotridge Stephanie ◽  
Sasidhar Uppuganti ◽  
Scott A. Guelcher ◽  
...  
Keyword(s):  
Finite Element Analysis ◽  
Finite Element ◽  
Fracture Healing ◽  
Bone Repair ◽  
Bone Fractures ◽  
Fracture Site ◽  
Fracture Repair ◽  
Long Bone ◽  
Design Parameters ◽  
Element Analysis

Abstract Delayed long bone fracture healing and nonunion continue to be a significant socioeconomic burden. While mechanical stimulation is known to be an important determinant of the bone repair process, understanding how the magnitude, mode, and commencement of interfragmentary strain (IFS) affect fracture healing can guide new therapeutic strategies to prevent delayed healing or non-union. Mouse models provide a means to investigate the molecular and cellular aspects of fracture repair, yet there is only one commercially available, clinically-relevant, locking intramedullary nail (IMN) currently available for studying long bone fractures in rodents. Having access to alternative IMNs would allow a variety of mechanical environments at the fracture site to be evaluated, and the purpose of this proof-of-concept finite element analysis study is to identify which IMN design parameters have the largest impact on IFS in a murine transverse femoral osteotomy model. Using the dimensions of the clinically relevant IMN as a guide, the nail material, distance between interlocking screws, and clearance between the nail and endosteal surface were varied between simulations. Of these parameters, changing the nail material from stainless steel (SS) to polyetheretherketone (PEEK) had the largest impact on IFS. Reducing the distance between the proximal and distal interlocking screws substantially affected IFS only when nail modulus was low. Therefore, IMNs with low modulus (e.g., PEEK) can be used alongside commercially available SS nails to investigate the effect of initial IFS or stability on fracture healing with respect to different biological conditions of repair in rodents.

scholarly journals Interactions between MSCs and Immune Cells: Implications for Bone Healing

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Tracy K. Kovach ◽  
Abhijit S. Dighe ◽  
Peter I. Lobo ◽  
Quanjun Cui
Keyword(s):  
Fracture Healing ◽  
Bone Healing ◽  
Immune Cells ◽  
Bone Repair ◽  
Repair Process ◽  
The United States ◽  
Fracture Repair ◽  
Cell Based Therapy

It is estimated that, of the 7.9 million fractures sustained in the United States each year, 5% to 20% result in delayed or impaired healing requiring therapeutic intervention. Following fracture injury, there is an initial inflammatory response that plays a crucial role in bone healing; however, prolonged inflammation is inhibitory for fracture repair. The precise spatial and temporal impact of immune cells and their cytokines on fracture healing remains obscure. Some cytokines are reported to be proosteogenic while others inhibit bone healing. Cell-based therapy utilizing mesenchymal stromal cells (MSCs) is an attractive option for augmenting the fracture repair process. Osteoprogenitor MSCs not only differentiate into bone, but they also exert modulatory effects on immune cells via a variety of mechanisms. In this paper, we review the current literature on bothin vitroandin vivostudies on the role of the immune system in fracture repair, the use of MSCs in the enhancement of fracture healing, and interactions between MSCs and immune cells. Insight into this paradigm can provide valuable clues in identifying cellular and noncellular targets that can potentially be modulated to enhance both natural bone healing and bone repair augmented by the exogenous addition of MSCs.

scholarly journals Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Gurpreet S. Baht ◽  
David Silkstone ◽  
Linda Vi ◽  
Puviindran Nadesan ◽  
Yasha Amani ◽  
...  
Keyword(s):  
Bone Repair ◽  
Repair Process ◽  
Osteoblastic Differentiation ◽  
Fracture Repair ◽  
Ageing Population ◽  
Haematopoietic Cells ◽  
Age Dependent ◽  
Old Mice

Abstract The capacity for tissues to repair and regenerate diminishes with age. We sought to determine the age-dependent contribution of native mesenchymal cells and circulating factors on in vivo bone repair. Here we show that exposure to youthful circulation by heterochronic parabiosis reverses the aged fracture repair phenotype and the diminished osteoblastic differentiation capacity of old animals. This rejuvenation effect is recapitulated by engraftment of young haematopoietic cells into old animals. During rejuvenation, β-catenin signalling, a pathway important in osteoblast differentiation, is modulated in the early repair process and required for rejuvenation of the aged phenotype. Temporal reduction of β-catenin signalling during early fracture repair improves bone healing in old mice. Our data indicate that young haematopoietic cells have the capacity to rejuvenate bone repair and this is mediated at least in part through β-catenin, raising the possibility that agents that modulate β-catenin can improve the pace or quality of fracture repair in the ageing population.

scholarly journals Molecular Mechanisms Controlling Bone Formation during Fracture Healing and Distraction Osteogenesis

2008 ◽  
Vol 87 (2) ◽  
pp. 107-118 ◽  
Author(s):  
Z.S. AI-Aql ◽  
A.S. Alagl ◽  
D.T. Graves ◽  
L.C. Gerstenfeld ◽  
T.A. Einhorn
Keyword(s):  
Fracture Healing ◽  
Distraction Osteogenesis ◽  
Transforming Growth Factor Beta ◽  
Bone Repair ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Fracture Repair ◽  
Relative Importance ◽  
Growth Factor Beta

Fracture healing and distraction osteogenesis have important applications in orthopedic, maxillofacial, and periodontal treatment. In this review, the cellular and molecular mechanisms that regulate fracture repair are contrasted with bone regeneration that occurs during distraction osteogenesis. While both processes have many common features, unique differences are observed in the temporal appearance and expression of specific molecular factors that regulate each. The relative importance of inflammatory cytokines in normal and diabetic healing, the transforming growth factor beta superfamily of bone morphogenetic mediators, and the process of angiogenesis are discussed as they relate to bone repair. A complete summary of biological activities and functions of various bioactive factors may be found at COPE (Cytokines & Cells Online Pathfinder Encyclopedia), http://www.copewithcytokines.de/cope.cgi .

scholarly journals Immunomodulatory Effects of MSCs in Bone Healing

2019 ◽  
Vol 20 (21) ◽  
pp. 5467 ◽  
Author(s):  
Dalia Medhat ◽  
Clara I. Rodríguez ◽  
Arantza Infante
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune System ◽  
Bone Repair ◽  
Human Mesenchymal Stem Cells ◽  
Cell Types ◽  
Bone Diseases ◽  
Fracture Repair ◽  
Innate Immune ◽  
A Cell

Mesenchymal stem cells (MSCs) are capable of differentiating into multilineage cells, thus making them a significant prospect as a cell source for regenerative therapy; however, the differentiation capacity of MSCs into osteoblasts seems to not be the main mechanism responsible for the benefits associated with human mesenchymal stem cells hMSCs when used in cell therapy approaches. The process of bone fracture restoration starts with an instant inflammatory reaction, as the innate immune system responds with cytokines that enhance and activate many cell types, including MSCs, at the site of the injury. In this review, we address the influence of MSCs on the immune system in fracture repair and osteogenesis. This paradigm offers a means of distinguishing target bone diseases to be treated with MSC therapy to enhance bone repair by targeting the crosstalk between MSCs and the immune system.

scholarly journals Treatment of critical defects produced in calvaria of mice with mesenchymal stem cells

2012 ◽  
Vol 84 (3) ◽  
pp. 841-851 ◽  
Author(s):  
Betânia S. Monteiro ◽  
Napoleão M. Argôlo-Neto ◽  
Nance B. Nardi ◽  
Pedro C. Chagastelles ◽  
Pablo H. Carvalho ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Bone Repair ◽  
Bone Matrix ◽  
Cell Types ◽  
Repair Process ◽  
Treated Group ◽  
Control Group ◽  
Calvarial Bone

Mesenchymal stem cells (MSC) are present in specialized niches in perivascular regions of adult tissues and are able to differentiate into various cell types, such as those committed to repairing. Bone marrow derived MSC from eight young mice C57BL/ 6 gfp+ were expanded in culture for repairing critical defects in calvarial bone produced in twenty-four young isogenic adult C57BL/6 mice. The animals were subjected to a cranial defect of 6.0mm diameter and divided into two equal experimental groups. Control group did not receive any treatment and the treated group received a MSC pellet containing 1.0 x 10(7) cells/mL into the defects. The group treated with MSC showed increased angiogenesis and amount of new bone deposited on the defect limits than that observed in the control group. The results demonstrated that transplantation of bone marrow-derived MSC of C57BL/6 gfp+ mice to bone critical defects produced in mice calvarial contributes positively to the bone repair process. MSC presets ability to influence the correct functioning of osteoblasts, increases the amount of mobilized cells for the repairing process, speeds up growth, and increases deposition of bone matrix.

scholarly journals Malnutrition and Fracture Healing: Are Specific Deficiencies in Amino Acids Important in Nonunion Development?

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1597 ◽  
Author(s):  
Dennis Meesters ◽  
Karolina Wijnands ◽  
Peter Brink ◽  
Martijn Poeze
Keyword(s):  
Nitric Oxide ◽  
Fracture Healing ◽  
Inflammatory Responses ◽  
Repair Process ◽  
Absolute Number ◽  
Fracture Repair ◽  
Influential Factor ◽  
Protein Amino Acid ◽  
Collagen Formation ◽  
Nitric Oxide Metabolism

With the increasing incidence of fractures now, and in the future, the absolute number of bone-healing complications such as nonunion development will also increase. Next to fracture-dependent factors such as large bone loss volumes and inadequate stabilization, the nutritional state of these patients is a major influential factor for the fracture repair process. In this review, we will focus on the influence of protein/amino acid malnutrition and its influence on fracture healing. Mainly, the arginine-citrulline-nitric oxide metabolism is of importance since it can affect fracture healing via several precursors of collagen formation, and through nitric oxide synthases it has influences on the bio-molecular inflammatory responses and the local capillary growth and circulation.

scholarly journals Systemic Administration of Recombinant Irisin Accelerates Fracture Healing in Mice

2021 ◽  
Vol 22 (19) ◽  
pp. 10863
Author(s):  
Silvia Concetta Colucci ◽  
Cinzia Buccoliero ◽  
Lorenzo Sanesi ◽  
Mariella Errede ◽  
Graziana Colaianni ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Mineral Content ◽  
Histological Analysis ◽  
Early Stage ◽  
Fold Increase ◽  
Repair Process ◽  
Fracture Repair ◽  
Bone Fracture Healing ◽  
Bony Callus ◽  
Callus Volume

To date, pharmacological strategies designed to accelerate bone fracture healing are lacking. We subjected 8-week-old C57BL/6 male mice to closed, transverse, mid-diaphyseal tibial fractures and treated them with intraperitoneal injection of a vehicle or r-irisin (100 µg/kg/weekly) immediately following fracture for 10 days or 28 days. Histological analysis of the cartilaginous callus at 10 days showed a threefold increase in Collagen Type X (p = 0.0012) and a reduced content of proteoglycans (40%; p = 0.0018). Osteoclast count within the callus showed a 2.4-fold increase compared with untreated mice (p = 0.026), indicating a more advanced stage of endochondral ossification of the callus during the early stage of fracture repair. Further evidence that irisin induced the transition of cartilage callus into bony callus was provided by a twofold reduction in the expression of SOX9 (p = 0.0058) and a 2.2-fold increase in RUNX2 (p = 0.0137). Twenty-eight days post-fracture, microCT analyses showed that total callus volume and bone volume were increased by 68% (p = 0.0003) and 67% (p = 0.0093), respectively, and bone mineral content was 74% higher (p = 0.0012) in irisin-treated mice than in controls. Our findings suggest that irisin promotes bone formation in the bony callus and accelerates the fracture repair process, suggesting a possible use as a novel pharmacologic modulator of fracture healing.

scholarly journals MAK122: A Novel Drug Utilizing Innovative Fracture Site Targeting Technology to Improve Bone Healing

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nicholas Hux ◽  
Jeffery Nielson ◽  
Caio De Andrade Staut ◽  
Vincent Alentado ◽  
Abduallah Elsayed ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Healing ◽  
Ex Vivo ◽  
Healing Process ◽  
Fracture Site ◽  
Fracture Repair ◽  
X Rays ◽  
Invasive Treatment ◽  
Post Surgery ◽  
Novel Drug

Megakaryocytes play a pivotal role in the bone fracture healing process through enhancing osteoblast proliferation, osteoclastogenesis, and angiogenesis. Current fracture repair therapies require direct implantation during surgery (BMP-2, grafts etc.), which has limitations. In order to address this, a novel drug, compound MAK122, was created with targeting technology that directs its actions to the fracture site without needing to be implanted during surgery, limiting undesirable offsite effects, increasing the quantity of drug at the fracture site, and allowing for non-invasive treatment following assessment of the natural healing process. Therefore, this study examined the ability of MAK122 to stimulate megakaryocytes and subsequent bone healing. To accomplish this, male mice on a C57BL/6 background underwent a surgically induced femoral fracture. Following surgery, the mice were injected daily for the first 7 days with either saline (vehicle) or MAK122. Mice were then euthanized 2, 3 and 4 weeks post-surgery.  Fracture healing was assessed by standard and novel methodologies. Biweekly X-rays were evaluated and bone union was scored showing that MAK122 accelerated bone healing compared to controls. Ex vivo µCT analysis demonstrated that MAK122 increased callus volume and the percentage of mineralized callus tissue compared to vehicle treatment. Biomechanical testing showed that MAK122 treatment resulted in stronger repairs as compared to vehicle treated controls with nearly a 2-fold increase in twist to failure and toughness parameters. Additionally, histological assessment demonstrated accelerated remodeling in MAK122 treated femurs compared to those treated with saline. Taken together, these pre-clinical data suggest that MAK122 is capable of promoting an environment in which megakaryocytes can favorably influence bone remodeling mechanisms, expediting fracture repair in murine models. Though further pharmacokinetic, pharmacodynamic, and toxicology studies are required, MAK122 displays potential to serve as a state-of-the-art therapy for improving fracture healing in humans.

scholarly journals Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Bas Molenaar ◽  
Louk T. Timmer ◽  
Marjolein Droog ◽  
Ilaria Perini ◽  
Danielle Versteeg ◽  
...  
Keyword(s):  
Single Cell ◽  
Communication Networks ◽  
Cardiac Remodeling ◽  
Cardiac Injury ◽  
Ischemic Injury ◽  
Cell Types ◽  
Repair Process ◽  
Cardiac Repair ◽  
Cellular Heterogeneity ◽  
Intercellular Signaling

AbstractThe efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. Furthermore, we established potential intercellular communication networks after ischemic injury. Follow up experiments confirmed that cardiomyocytes express and secrete elevated levels of beta-2 microglobulin in response to ischemic damage, which can activate fibroblasts in a paracrine manner. Collectively, our data indicate phase-specific changes in cellular heterogeneity during different stages of cardiac remodeling and allow for the identification of therapeutic targets relevant for cardiac repair.

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