Men who stare at bone: multimodal monitoring of bone healing

Abstract Knowledge of the physiological and pathological processes, taking place in bone during fracture healing or defect regeneration, is essential in order to develop strategies to enhance bone healing under normal and critical conditions. Preclinical testing allows a wide range of imaging modalities that may be applied both simultaneously and longitudinally, which will in turn lower the number of animals needed to allow a comprehensive assessment of the healing process. This work provides an up-to-date review on morphological, functional, optical, biochemical, and biophysical imaging techniques including their advantages, disadvantages and potential for combining them in a multimodal and multiscale manner. The focus lies on preclinical testing of biomaterials modified with artificial extracellular matrices in various animal models to enhance bone remodeling and regeneration.

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

Biomedicines ◽

10.3390/biomedicines9060691 ◽

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.

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Fracture Healing and Biomarker Expression in a Diabetic Zucker Rat Model

Journal of the American Podiatric Medical Association ◽

10.7547/0003-0538-104.5.428 ◽

2014 ◽

Vol 104 (5) ◽

pp. 428-433 ◽

Cited By ~ 6

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.

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Influence of high-frequency cyclical stimulation on the bone fracture-healing process: mathematical and experimental models

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2011.0153 ◽

2011 ◽

Vol 369 (1954) ◽

pp. 4278-4294 ◽

Cited By ~ 16

Author(s):

María José Gómez-Benito ◽

Libardo Andrés González-Torres ◽

Esther Reina-Romo ◽

Jorge Grasa ◽

Belén Seral ◽

...

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Mechanical Stimulation ◽

Bone Fracture ◽

High Frequency ◽

Endochondral Ossification ◽

Healing Process ◽

Bone Fracture Healing ◽

Bone Healing Process ◽

Low Magnitude

Mechanical stimulation affects the evolution of healthy and fractured bone. However, the effect of applying cyclical mechanical stimuli on bone healing has not yet been fully clarified. The aim of the present study was to determine the influence of a high-frequency and low-magnitude cyclical displacement of the fractured fragments on the bone-healing process. This subject is studied experimentally and computationally for a sheep long bone. On the one hand, the mathematical computational study indicates that mechanical stimulation at high frequencies can stimulate and accelerate the process of chondrogenesis and endochondral ossification and consequently the bony union of the fracture. This is probably achieved by the interstitial fluid flow, which can move nutrients and waste from one place to another in the callus. This movement of fluid modifies the mechanical stimulus on the cells attached to the extracellular matrix. On the other hand, the experimental study was carried out using two sheep groups. In the first group, static fixators were implanted, while, in the second one, identical devices were used, but with an additional vibrator. This vibrator allowed a cyclic displacement with low magnitude and high frequency (LMHF) to be applied to the fractured zone every day; the frequency of stimulation was chosen from mechano-biological model predictions. Analysing the results obtained for the control and stimulated groups, we observed improvements in the bone-healing process in the stimulated group. Therefore, in this study, we show the potential of computer mechano-biological models to guide and define better mechanical conditions for experiments in order to improve bone fracture healing. In fact, both experimental and computational studies indicated improvements in the healing process in the LMHF mechanically stimulated fractures. In both studies, these improvements could be associated with the promotion of endochondral ossification and an increase in the rate of cell proliferation and tissue synthesis.

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Current Options for Determining Fracture Union

Advances in Medicine ◽

10.1155/2014/708574 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 76

Author(s):

Saam Morshed

Keyword(s):

Bone Healing ◽

Imaging Techniques ◽

Healing Process ◽

Fracture Union ◽

Patient Centered ◽

Multiple Modalities ◽

Practical Research ◽

Significant Disagreement ◽

And Function

Determining whether a bone fracture is healed is one of the most important and fundamental clinical determinations made in orthopaedics. However, there are currently no standardized methods of assessing fracture union, which in turn has created significant disagreement among orthopaedic surgeons in both clinical and research settings. An extensive amount of research has been dedicated to finding novel and reliable ways of determining healing with some promising results. Recent advancements in imaging techniques and introduction of new radiographic scores have helped decrease the amount of disagreement on this topic among physicians. The knowledge gained from biomechanical studies of bone healing has helped us refine our tools and create more efficient and practical research instruments. Additionally, a deeper understanding of the molecular pathways involved in the bone healing process has led to emergence of serologic markers as possible candidates in assessment of fracture union. In addition to our current physician centered methods, patient-centered approaches assessing quality of life and function are gaining popularity in assessment of fracture union. Despite these advances, assessment of union remains an imperfect practice in the clinical setting. Therefore, clinicians need to draw on multiple modalities that directly and indirectly measure or correlate with bone healing when counseling patients.

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CLINICAL APPLICATION OF BONE MORPHOGENETIC PROTEIN ON FRACTURE HEALING PROCESS

(JOINTS) Journal Orthopaedi and Traumatology Surabaya ◽

10.20473/joints.v6i2.2017.48-54 ◽

2019 ◽

Vol 6 (2) ◽

pp. 48

Author(s):

Riko Febrian Kunta Adjie

Keyword(s):

Fracture Healing ◽

Clinical Application ◽

Bone Morphogenetic Proteins ◽

Bone Healing ◽

Healing Process ◽

Delayed Union ◽

Non Union ◽

Morphogenetic Protein ◽

Number Of Patients ◽

And Function

Delayed union or non-union often occurs in bone healing fracture process. The clinical application of Bone Morphogenetic Proteins (BMPs) has helped an increasing number of patients achieve bone regeneration in clinical area lacking simple solutions for difficult bone healing situations. Many researches has proved that BMPs improved fracture healing regeneration. In this review article, introduction and current clinical issues are summarized on efficacy and function of BMPs. Currently, rhBMP-2 and rhBMP-7 have shown clinical significance but other subfamily members of BMPs still lacked of evidence.

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Influence of Smoking in the Clinical Outcomes of Distal Radius Fractures

Journal of Hand and Microsurgery ◽

10.1055/s-0040-1715425 ◽

2020 ◽

Author(s):

Ayaka Kaneko ◽

Kiyohito Naito ◽

Hiroyuki Obata ◽

Nana Nagura ◽

Yoichi Sugiyama ◽

...

Keyword(s):

Fracture Healing ◽

Range Of Motion ◽

Distal Radius Fracture ◽

Distal Radius ◽

Bone Healing ◽

Fracture Fixation ◽

Healing Process ◽

Distal Radius Fractures ◽

Radius Fracture ◽

Radius Fractures

Abstract Introduction There are various studies that reviewed the effect of cigarette smoking in fracture healing process. Nonunion, delayed union, and residual pain are the significant risk factors associated with smoking and fracture healing. Little has been known about the impact of smoking in distal radius fracture healing. We intend to explore in brief the effect of smoking in distal radius fracture healing and comparing it with nonsmokers having the same fracture fixation and analyze the outcomes with respect to fracture healing and return of function. Materials and Methods Of the total 186 patients, 92 were included in the study with (n = male: 31, female: 61) mean age of 60.2 years. They were divided into two groups: smoking (n = 43) and nonsmoking (n = 49). All had surgical fixation of the distal radius with volar locking plate and started on early mobilization. The range of motion of the wrist, grip, visual analog scale, quick disabilities of the arm and shoulder and hand score, Mayo wrist score, and bone healing period were noted between these two groups and compared with statistical analysis. Results The mean follow-up period was 8.7 months. There was a significant association of young age and male patients having distal radius fractures in the smoking group (p < 0.05). All fractures healed well in both groups without complications. There was no significant difference between these two groups in terms of range of motion, grasp, bone healing period, and functional outcomes. Conclusion Despite the well-known fact that, smoking has negative implications in the fracture healing process, we found group of patients (smoking and nonsmoking) with distal radius fractures treated by volar locking plates healed well with good radiological union and excellent functional outcome There is no significant influence of smoking in distal radius fracture fixation.

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Simulating Metaphyseal Fracture Healing in the Distal Radius

Biomechanics ◽

10.3390/biomechanics1010003 ◽

2021 ◽

Vol 1 (1) ◽

pp. 29-42

Author(s):

Lucas Engelhardt ◽

Frank Niemeyer ◽

Patrik Christen ◽

Ralph Müller ◽

Kerstin Stock ◽

...

Keyword(s):

Fracture Healing ◽

Distal Radius ◽

Bone Healing ◽

Numerical Models ◽

Healing Process ◽

Patient Specific ◽

Diaphyseal Fracture ◽

Metaphyseal Fracture ◽

Metaphyseal Bone ◽

Metaphyseal Fracture Healing

Simulating diaphyseal fracture healing via numerical models has been investigated for a long time. It is apparent from in vivo studies that metaphyseal fracture healing should follow similar biomechanical rules although the speed and healing pattern might differ. To investigate this hypothesis, a pre-existing, well-established diaphyseal fracture healing model was extended to study metaphyseal bone healing. Clinical data of distal radius fractures were compared to corresponding geometrically patient-specific fracture healing simulations. The numerical model, was able to predict a realistic fracture healing process in a wide variety of radius geometries. Endochondral and mainly intramembranous ossification was predicted in the fractured area without callus formation. The model, therefore, appears appropriate to study metaphyseal bone healing under differing mechanical conditions and metaphyseal fractures in different bones and fracture types. Nevertheless, the outlined model was conducted in a simplified rotational symmetric case. Further studies may extend the model to a three-dimensional representation to investigate complex fracture shapes. This will help to optimize clinical treatments of radial fractures, medical implant design and foster biomechanical research in metaphyseal fracture healing.

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Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing

International Journal of Molecular Sciences ◽

10.3390/ijms21030865 ◽

2020 ◽

Vol 21 (3) ◽

pp. 865 ◽

Cited By ~ 4

Author(s):

Timo Gaber ◽

Antonia Clara Katharina Brinkman ◽

Justyna Pienczikowski ◽

Karoline Diesing ◽

Alexandra Damerau ◽

...

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Positive Impact ◽

Healing Process ◽

Osteoclast Differentiation ◽

Janus Kinase ◽

Inflammatory Microenvironment ◽

Positive Effects ◽

Anti Inflammatory

Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10–100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely.

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Evaluation of Bone Healing Using Contrast-Enhanced Ultrasonography in Non-Operative Treatment of Tibial Fracture in a Puppy Dog

Animals ◽

10.3390/ani11020284 ◽

2021 ◽

Vol 11 (2) ◽

pp. 284

Author(s):

Francesco Macrì ◽

Vito Angileri ◽

Teresa Russo ◽

Maria Tomiko Russo ◽

Marco Tabbì ◽

...

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Tibial Fracture ◽

Callus Formation ◽

Color Doppler ◽

Healing Process ◽

Power Doppler ◽

Low Velocity ◽

Blood Flows ◽

Contrast Enhanced

A 10-month-old mixed-breed male dog was presented with an oblique tibial fracture. The dog was treated with a Robert Jones-like bandage as a conservative approach, and was subjected to X-ray, B-mode, Color Doppler and contrast-enhanced ultrasound (CEUS) examinations during the fracture healing, in order to assess bone hemodynamic changes. B-mode, Power Doppler and CEUS examinations of the fracture gap were performed at 7, 20, 35, and 50 days post-trauma. Quantitative analysis of CEUS and perfusion parameters were obtained. On CEUS, a steep incline in signal numbers was visible in fracture gap at 7 days with peaks at 35 days, after which the vascularization decreases gradually over the next days. In this study, CEUS provided important information on the early stages of the callus formation and on the healing of neighboring tissues, allowing recognition of a correct bone healing. Moreover, the number of vascular signals on CEUS was greater than that on Doppler images on the same day. This report showed the application of CEUS in controlling the fracture healing process. CEUS could be a method of monitoring the remedial processes, assessing the tibial fracture perfusion characterized by low-velocity, small-volume blood flows.

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176 Patient Perception on Fracture Healing

British Journal of Surgery ◽

10.1093/bjs/znab134.239 ◽

2021 ◽

Vol 108 (Supplement_2) ◽

Author(s):

Z Sadozai ◽

S A Bokhari ◽

K Mannan

Keyword(s):

Fracture Healing ◽

Communication Skills ◽

Bone Healing ◽

Healing Process ◽

Harmful Effect ◽

Patient Perception ◽

Lifestyle Modifications ◽

Single Centre ◽

Good Medical Practice ◽

The Uk

Abstract Introduction Effective communication skills are an extremely important aspect of good medical practice. Fractures are common with over 1 million fractures occurring each year in the UK; of which 5-10% may have problems with healing. Patient perceptions of factors harmful to the fracture healing process are unknown and our study investigates this. Method A total of 418 responses were collected from participants in a single centre in our survey based study to determine patient perception on factors potentially affecting bone-healing. Results 84% and 73% of patients believed tobacco and alcohol to be harmful to bone-healing. 31% thought that there was a harmful effect to bone-healing with ibuprofen and 25% perceived the same regarding caffeine. Paracetamol, vinegar, and chocolate were considered to be least harmful to bone-healing with 20%,15% and 11% responses respectively. Conclusions The majority of patients believed that there was a harmful association with tobacco and alcohol with regards to bone-healing. This harmful relationship is well understood in literature. However, we believe for the benefit of patients, they should all be aware of these detrimental effects. A clear possibility has been identified to improve fracture outcomes by empowering patients to take ownership of their injury by lifestyle modifications which are within their remit.

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