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 Novel Fracture Site Targeting Drug Improves Fracture Healing with Pain Relief: Preclinical Evaluation of MAK123

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Abduallah Elsayed ◽  
Jeffery Nielsen ◽  
Natalie Taylor ◽  
Mohammed Juboori ◽  
Caio de Andrade Staut ◽  
...  
Keyword(s):  
Bone Healing ◽  
Femoral Fracture ◽  
Ex Vivo ◽  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Fracture Site ◽  
X Rays ◽  
Opioid Use ◽  
Fracture Callus ◽  
Surgically Induced

Non-union bone fracture occurs in 5-10% of fracture injuries. Interventions include surgery with local implantation of autograft, allograft, demineralized bone matrix, and/or bone morphogenetic proteins. These types of fracture injuries are also accompanied by acute and chronic pain states. In most instances, opioids are provided to injured patients during and after surgery. With the opioid crisis, identifying new analgesic therapies that could reduce or eliminate opioid use, while also improving bone healing is important. Here we show the ability of a novel compound, MAK123, to both enhance bone healing and reduce pain behavior in a surgically induced femoral fracture mouse model. Briefly, 20 male C57BL/6 mice underwent a surgically induced femoral fracture and then were treated with 0, 2, 6, or 20 mg/kg, 3X/week for the 3 week study duration. Weekly X-rays were used to examine healing progression. Prior to euthanasia, mice underwent behavioral testing to measure evoked pain behaviors. Upon euthanasia, ex vivo µCT imaging and analysis was completed to assess fracture callus size and composition. While all doses of MAK123 tested resulted in improved healing, the 6mg/kg dose resulted in accelerated bone healing and a significant increase in mineralized callus volume (p<0.05). Similarly, while all doses of MAK123 reduced evoked responses to tactile stimulus as demonstrated by increased paw withdrawal thresholds, 6 mg/kg of MAK123 resulted in a more robust and significant improvement (p<0.05). We postulate that optimization of the dosing schedule/concentration could further improve both bone healing and behavioral measures thought to represent pain in rodents. That said, these promising pre-clinical data warrant further evaluation as MAK123 may prove to be a unique tool for orthopaedic surgery usage whereby it could both improve bone healing and reduce clinical pain, improving overall patient outcomes.  

scholarly journals Correlating mRUST scoring with fracture healing in the mouse model

2020 ◽  
Vol 3 ◽  
Author(s):  
Anthony McGuire ◽  
Adam Knox ◽  
Caio de Andrade Staut ◽  
Melissa Kacena ◽  
Roman Natoli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fracture Healing ◽  
Bone Fractures ◽  
Healing Process ◽  
Fracture Repair ◽  
Long Bone ◽  
Post Surgery ◽  
Method Of Assessment ◽  
Non Destructive

Background/Objective: Long bone fractures are an expensive and frequent cause of disability in humans. Research seeking to accelerate and improve the healing process is more essential than ever. Animal models, mice especially, provide an inexpensive and reproducible model of in vivo fracture healing. However, many measures of murine fracture healing outcomes are either expensive or destructive, limiting their ability to be translated to clinical studies. We seek to determine how these measures such as biomechanics, µCT, and histology correlate to the relatively new, inexpensive, and non-destructive method of mRUST scoring in a mouse model.  Methods: One hundred and thirty-five, 12-week old male C57BL6/J mice were divided into nine groups of 15 mice. Mice underwent a surgically created, femoral fracture. At biweekly timepoints, anteroposterior and lateral radiographs were taken, and 15 mice were sacrificed at each time point (7, 10, 14, 17, 21, 24, 28, 35, and 42 days post-surgery) for biomechanical, µCT, and histological analyses. The modified Radiographic Union Scale for Tibial fractures (mRUST scoring) provides a score based on the visualization of a callus and fracture line in four cortices on the radiographs. Data analysis will be performed to determine the degree of correlation between mRUST scoring and other fracture healing outcomes.  Results/Conclusion: Data collection in this experiment is still forthcoming. Upon successful completion of this project, we will have established numerical correlations between mRUST scoring and other fracture healing outcomes, such as biomechanics, µCT microarchitecture, and histology. These correlations will provide a powerful tool in future mouse fracture healing studies, as data on the state and strength of fracture repair could be determined by simple radiograph.  Scientific/Clinical Policy Impact and Implications: This study will both provide future murine fracture studies with an inexpensive and non-destructive method of assessment that is more directly translatable to human fracture studies. 

scholarly journals Can Optimizing the Mechanical Environment Deliver a Clinically Significant Reduction in Fracture Healing Time?

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 691
Author(s):  
Jan Barcik ◽  
Devakara R. Epari
Keyword(s):  
Fracture Healing ◽  
Bone Healing ◽  
Mechanical Stimulation ◽  
Callus Formation ◽  
Weight Bearing ◽  
Healing Process ◽  
Healing Time ◽  
Mechanical Environment ◽  
Clinically Significant ◽  
The Impact

The impact of the local mechanical environment in the fracture gap on the bone healing process has been extensively investigated. Whilst it is widely accepted that mechanical stimulation is integral to callus formation and secondary bone healing, treatment strategies that aim to harness that potential are rare. In fact, the current clinical practice with an initially partial or non-weight-bearing approach appears to contradict the findings from animal experiments that early mechanical stimulation is critical. Therefore, we posed the question as to whether optimizing the mechanical environment over the course of healing can deliver a clinically significant reduction in fracture healing time. In reviewing the evidence from pre-clinical studies that investigate the influence of mechanics on bone healing, we formulate a hypothesis for the stimulation protocol which has the potential to shorten healing time. The protocol involves confining stimulation predominantly to the proliferative phase of healing and including adequate rest periods between applications of stimulation.

Clinical efficacy of autogenous cancellous bone and fibroblast growth factor 2 combined with frozen allografts in femoral nonunion fractures

2013 ◽  
Vol 26 (02) ◽  
pp. 123-129 ◽  
Author(s):  
H. Ochi ◽  
N. Kannno ◽  
M. Iwata ◽  
T. Ichinohe ◽  
Y. Harada ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cancellous Bone ◽  
Healing Process ◽  
Fracture Repair ◽  
Fibroblast Growth Factor 2 ◽  
Fibroblast Growth ◽  
Post Surgery ◽  
Femoral Shortening ◽  
Cortical Allograft

SummaryObjectives: To evaluate the efficacy of cortical allograft and fibroblast growth factor 2 (FGF-2)-impregnated autogenous cancellous bone in nonunion fracture repair in dogs.Methods: From January 2000 to August 2010, seven dogs underwent cortical allograft and FGF-2-impregnated autogenous cancellous bone implantation for treatment of a femoral nonunion following fracture. Radiographic images were used to assess healing.Results: The average length of the implanted cortical allograft was 29.1 ± 4.4 mm. A significant improvement in the postoperative percentage of femoral shortening was observed with the experimental treatment, from 85.2 ± 8.2% to 95.0 ± 4.8%. Using radiographic scoring, we analysed the process of bone remodelling. At three months post-surgery, the proximal and distal fracture lines had begun to disappear, and a complete absence was observed after six months. Bacterial infection was detected in two of the seven cases.Clinical significance: The findings of our study suggest that the combination of cortical allografts with FGF-2 impregnated cancellous autograft may be useful in cases of diaphyseal fracture non-union. The disappearance of the fracture line in dogs with nonunion was recognized at the same phase as the report in which healing process of allograft was evaluated in the experimental ostectomy model using the normal dog.

scholarly journals A novel MRI compatible mouse fracture model to characterize and monitor bone regeneration and tissue composition

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nina Schmitz ◽  
Melanie Timmen ◽  
Katharina Kostka ◽  
Verena Hoerr ◽  
Christian Schwarz ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Regeneration ◽  
Cell Attachment ◽  
Healing Process ◽  
Living Organism ◽  
Fracture Site ◽  
Tissue Composition ◽  
Metal Implants ◽  
Callus Tissues

Abstract Over the last years, murine in vivo magnetic resonance imaging (MRI) contributed to a new understanding of tissue composition, regeneration and diseases. Due to artefacts generated by the currently used metal implants, MRI is limited in fracture healing research so far. In this study, we investigated a novel MRI-compatible, ceramic intramedullary fracture implant during bone regeneration in mice. Three-point-bending revealed a higher stiffness of the ceramic material compared to the metal implants. Electron microscopy displayed a rough surface of the ceramic implant that was comparable to standard metal devices and allowed cell attachment and growth of osteoblastic cells. MicroCT-imaging illustrated the development of the callus around the fracture site indicating a regular progressing healing process when using the novel implant. In MRI, different callus tissues and the implant could clearly be distinguished from each other without any artefacts. Monitoring fracture healing using MRI-compatible implants will improve our knowledge of callus tissue regeneration by 3D insights longitudinal in the same living organism, which might also help to reduce the consumption of animals for future fracture healing studies, significantly. Finally, this study may be translated into clinical application to improve our knowledge about human bone regeneration.

scholarly journals Endogenous Production of n-3 Polyunsaturated Fatty Acids Promotes Fracture Healing in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Yuhui Chen ◽  
He Cao ◽  
Dawei Sun ◽  
Changxin Lin ◽  
Liang Wang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Fracture Healing ◽  
Histological Analysis ◽  
Callus Formation ◽  
Healing Process ◽  
Proximal Femoral Fracture ◽  
Fracture Repair ◽  
Micro Ct ◽  
Micro Computed Tomography ◽  
X Ray

Bone fracture is a global healthcare issue for high rates of delayed healing and nonunions. Although n-3 polyunsaturated fatty acid (PUFA) is considered as a beneficial factor for bone metabolism, only few studies till date focused on the effects of n-3 PUFAs on fracture healing. In this study, we investigated the effect of endogenous n-3 PUFAs on fracture healing by measuring femur fracture repair in bothfat-1transgenic mice and WT mice. Proximal femoral fracture model was established infat-1transgenic mice and WT mice, respectively, and then the fracture was analyzed by using X-ray, micro-computed tomography (micro-CT), and histological assessment at 7, 14, 21, 28, and 35 days after fixation. The results showed that compared with WT mice,fat-1mice exhibited acceleration in fracture healing through radiographic and histological analysis (18–21 days versus 21–28 days postfracture). Meanwhile, X-ray and micro-CT analysis that showed better remodeling callus formation were in thefat-1group compared to WT group. Furthermore, histological analysis revealed that endogenous n-3 PUFAs promoted local endochondral ossification and accelerated the remodeling of calcified calluses after fracture. In conclusion, the present study indicated that endogenously produced n-3 PUFAs promote fracture healing process and accelerate bone remodeling in mice, and supplementation of n-3 PUFAs was positively associated with fracture healing.

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.

Fracture Healing and Biomarker Expression in a Diabetic Zucker Rat Model

2014 ◽  
Vol 104 (5) ◽  
pp. 428-433 ◽  
Author(s):  
Javier La Fontaine ◽  
Nathan A. Hunt ◽  
Stacey Curry ◽  
Tyler Kearney ◽  
Daniel Jupiter ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Fracture Healing ◽  
Bone Healing ◽  
Rat Model ◽  
Healing Process ◽  
Diabetic Rats ◽  
Vascular Endothelial ◽  
Delayed Healing ◽  
Endothelial Growth Factor

Background Persons with diabetes have a higher incidence of fractures compared with persons without diabetes. However, there is little published information concerning the deleterious effect of late-stage diabetes on fracture healing. There are no studies using animal models that evaluate the effect of advanced diabetes on fracture healing. The purpose of our study was to evaluate cytokine expression, specifically macrophage inflammatory protein 1 (MIP-1) and vascular endothelial growth factor, in fracture healing in a type 2 diabetes rat model. Methods We evaluated biomarker expression after femur fracture using a rat model. The two groups consisted of 24 Zucker diabetic rats (study group) and 12 Zucker lean rats (control group). An independent reviewer was used to assess delayed union. We evaluated serum samples 2, 4, 7, and 14 days after surgery for MIP-1, vascular endothelial growth factor, leptin, and other cytokine levels. Results At 3 weeks, Kaplan-Meier estimates showed that 45.8% of femur fractures in Zucker diabetic rats had healed, whereas 81.8% of those in Zucker lean rats had healed (P = .02). A logistic regression model to predict fast healing that included the three cytokines and diabetes status showed that the only factor achieving significance was MIP-1α. Vascular endothelial growth factor was the only biomarker to show significance compared with delayed healing. Conclusions These results confirm significant differences in biomarker expression between diabetic and nondiabetic rats during bone healing. The key factors for bone healing may appear early in the healing process, whereas differences in diabetes versus nondiabetes are seen later in the healing process. Increased levels of MIP-1α were associated with the likelihood of delayed healing.

scholarly journals Tibia Fracture Healing Prediction Using First-Order Mathematical Model

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
M. Sridevi ◽  
P. Prakasam ◽  
S. Kumaravel ◽  
P. Madhava Sarma
Keyword(s):  
Mathematical Model ◽  
Fracture Healing ◽  
Fracture Site ◽  
Tibia Fracture ◽  
Model Parameters ◽  
X Rays ◽  
Electric Voltage ◽  
First Order ◽  
Healing Period ◽  
Process Gain

The prediction of healing period of a tibia fracture in humans across limb using first-order mathematical model is demonstrated. At present, fracture healing is diagnosed using X-rays. Recent studies have demonstrated electric stimulation as a diagnostic tool in fracture healing. A DC electric voltage of 0.7 V was applied across the fracture and stabilized with Teflon coated carbon rings and the data was recorded at different time intervals until the fracture heals. The experimental data fitted a first-order plus dead time zero model (FOPDTZ) that coincided with the mathematical model of electrical simulated tibia fracture limb. Fracture healing diagnosis was proposed using model parameter process gain. Current stabilization in terms of process gain parameter becoming constant indicates that the healing of fracture is a new finding in the work. An error analysis was performed and it was observed that the measured data correlated to the FOPDTZ model with an error of less than 2 percent. Prediction of fracture healing period was done by one of the identified model parameters, namely, process gain. Moreover, mathematically, it is justified that once the fracture is completely united there is no capacitance present across the fracture site, which is a novelty of the work.

scholarly journals Exogenous PTH 1-34 Attenuates Impaired Fracture Healing in Endogenous PTH Deficiency Mice via Activating Indian Hedgehog Signaling Pathway and Accelerating Endochondral Ossification

2022 ◽  
Vol 9 ◽  
Author(s):  
Cheng Ma ◽  
Huan Liu ◽  
Yifan Wei ◽  
He Li ◽  
Dengshun Miao ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Signaling Pathway ◽  
Endochondral Ossification ◽  
Healing Process ◽  
Fracture Repair ◽  
Luciferase Reporter ◽  
Endochondral Bone Formation ◽  
Fracture Callus ◽  
Endochondral Bone ◽  
Bony Callus

Fracture healing is a complicated, long-term, and multistage repair process. Intermittent administration of parathyroid hormone (PTH) has been proven effective on intramembranous and endochondral bone formation during the fracture healing process, however, the mechanism is unclear. In this study, we investigated the role of exogenous PTH and endogenous PTH deficiency in bone fracture healing and explored the mechanism by using PTH knockout (PTH-/-) mice and ATDC5 cells. In a mouse femur fracture model, endogenous PTH deficiency could delay endochondral ossification whereas exogenous PTH promotes accumulation of endochondral bone, accelerates cartilaginous callus conversion to bony callus, enhances maturity of bony callus, and attenuates impaired fracture healing resulting from endogenous PTH deficiency. In fracture callus tissue, endogenous PTH deficiency could inhibit chondrocyte proliferation and differentiation whereas exogenous PTH could activate the IHH signaling pathway to accelerate endochondral ossification and rescue impaired fracture healing resulting from endogenous PTH deficiency. In vitro, exogenous PTH promotes cell proliferation by activating IHH signaling pathway on ATDC5 cells. In mechanistic studies, by using ChIP and luciferase reporter assays, we showed that PTH could phosphorylate CREB, and subsequently bind to the promoter of IHH, causing the activation of IHH gene expression. Therefore, results from this study support the concept that exogenous PTH 1-34 attenuates impaired fracture healing in endogenous PTH deficiency mice via activating the IHH pathway and accelerating endochondral ossification. Hence, the investigation of the mechanism underlying the effects of PTH treatment on fracture repair might guide the exploration of effective therapeutic targets for fracture.

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