A vascularized bone-on-a-chip model development via exploring mechanical stimulation for evaluation of fracture healing therapeutics

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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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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Controlled Cyclic Compression of an Open Tibial Fracture Using an External Fixator Affects Fracture Healing in Mice

Journal of Biomechanical Engineering ◽

10.1115/1.4029983 ◽

2015 ◽

Vol 137 (5) ◽

Cited By ~ 3

Author(s):

Jennifer A. Currey ◽

Megan Mancuso ◽

Sylvie Kalikoff ◽

Erin Miller ◽

Sean Day

Keyword(s):

Fracture Healing ◽

Mechanical Stimulation ◽

External Fixator ◽

Qualitative Assessment ◽

Control Group ◽

External Fixators ◽

Tibial Osteotomy ◽

Micro Computed Tomography ◽

Trabecular Thickness ◽

Significant Difference

Fractures resulting in impaired healing can be treated with mechanical stimulation via external fixators. To examine the effect of mechanical stimulation on fracture healing, we developed an external fixator for use in a mouse model. A 0.5 mm tibial osteotomy was stabilized with the external fixator in C57BL/6 mice. Osteotomies in the treatment group (nt = 41) were subjected to daily sessions of 150 μm of controlled displacement with the aim to create a more mineralized callus at 21 days compared with the control group (nc = 39). Qualitative assessment of the histology found no notable difference in healing patterns between groups at 7, 12, 17, and 21 days. At 21 days, micro-computed tomography (CT) analysis showed that the control group had a significantly higher bone volume (BV) fraction and trabecular number compared with treatment; however there was no significant difference in the total volume (TV) of the callus or trabecular thickness between groups. In summary, the external fixator was used with a motion application system to apply controlled displacement to a healing fracture; however, this treatment did not result in a more mineralized callus at 21 days.

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Pronator quadratus pedicled bone graft for scaphoid non-unions

International Surgery Journal ◽

10.18203/2349-2902.isj20203960 ◽

2020 ◽

Vol 7 (10) ◽

pp. 3414

Author(s):

Harsha Vardhan ◽

Anto Francis

Keyword(s):

Bone Graft ◽

Fracture Healing ◽

Scaphoid Fracture ◽

Fracture Site ◽

Vascularized Bone Graft ◽

Proximal Pole ◽

Pronator Quadratus ◽

Scaphoid Fractures ◽

Fracture Nonunion ◽

Vascularized Bone

Scaphoid fractures frequently present with nonunion and proximal pole necrosis, the treatment of which is bone grafting. Pronator quadratus pedicled vascularized bone graft is an option especially in the setting of proximal pole necrosis. We describe our experience of managing such scaphoid non-unions using pronator quadratus pedicled vascularized bone graft. Six patients were managed using pronator quadratus pedicled vascularized bone graft following scaphoid fracture nonunion with proximal pole necrosis. All patients had good fracture healing and symptom resolution. Mild deficit in wrist extension was noted in all patients. Pronator quadratus pedicled vascularized bone graft is an attractive option for managing scaphoid nonunion. Lying adjacent to the fracture site, bone can be harvested and transferred without making any other incisions. This procedure introduces another source of blood supply to the fracture site and hence improves fracture healing.

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Experimental Study on the Effect of Mechanical Stimulation on the Early Stage of Fracture Healing

Journal of Nippon Medical School ◽

10.1272/jnms.71.252 ◽

2004 ◽

Vol 71 (4) ◽

pp. 252-262 ◽

Cited By ~ 4

Author(s):

Tomomichi Takeda ◽

Tetsuya Narita ◽

Hiromoto Ito

Keyword(s):

Experimental Study ◽

Fracture Healing ◽

Mechanical Stimulation ◽

Early Stage

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Acute Inflammatory Response in Osteoporotic Fracture Healing Augmented with Mechanical Stimulation is Regulated In Vivo through the p38-MAPK Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22168720 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8720

Author(s):

Simon Kwoon Ho Chow ◽

Can Cui ◽

Keith Yu Kin Cheng ◽

Yu Ning Chim ◽

Jinyu Wang ◽

...

Keyword(s):

Inflammatory Response ◽

Fracture Healing ◽

P38 Mapk ◽

Osteoporotic Fracture ◽

Mechanical Stimulation ◽

Mapk Pathway ◽

Acute Inflammatory Response ◽

P38 Mapk Pathway ◽

Response Expression

Low-magnitude high-frequency vibration (LMHFV) has previously been reported to modulate the acute inflammatory response of ovariectomy-induced osteoporotic fracture healing. However, the underlying mechanisms are not clear. In the present study, we investigated the effect of LMHFV on the inflammatory response and the role of the p38 MAPK mechanical signaling pathway in macrophages during the healing process. A closed femoral fracture SD rat model was used. In vivo results showed that LMHFV enhanced activation of the p38 MAPK pathway at the fracture site. The acute inflammatory response, expression of inflammatory cytokines, and callus formation were suppressed in vivo by p38 MAPK inhibition. However, LMHFV did not show direct in vitro enhancement effects on the polarization of RAW264.7 macrophage from the M1 to M2 phenotype, but instead promoted macrophage enlargement and transformation to dendritic monocytes. The present study demonstrated that p38 MAPK modulated the enhancement effects of mechanical stimulation in vivo only. LMHFV may not have exerted its enhancement effects directly on macrophage, but the exact mechanism may have taken a different pathway that requires further investigation in the various subsets of immune cells.

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Mechanical stimulation enhanced estrogen receptor expression and callus formation in diaphyseal long bone fracture healing in ovariectomy-induced osteoporotic rats

Osteoporosis International ◽

10.1007/s00198-016-3619-2 ◽

2016 ◽

Vol 27 (10) ◽

pp. 2989-3000 ◽

Cited By ~ 16

Author(s):

S. K. H. Chow ◽

K. S. Leung ◽

J. Qin ◽

A. Guo ◽

M. Sun ◽

...

Keyword(s):

Estrogen Receptor ◽

Fracture Healing ◽

Mechanical Stimulation ◽

Bone Fracture ◽

Callus Formation ◽

Receptor Expression ◽

Long Bone ◽

Estrogen Receptor Expression ◽

Bone Fracture Healing ◽

Long Bone Fracture

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Short-Term Bone Healing Response to Mechanical Stimulation—A Case Series Conducted on Sheep

Biomedicines ◽

10.3390/biomedicines9080988 ◽

2021 ◽

Vol 9 (8) ◽

pp. 988

Author(s):

Jan Barcik ◽

Manuela Ernst ◽

Marc Balligand ◽

Constantin Edmond Dlaska ◽

Ludmil Drenchev ◽

...

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Mechanical Stimulation ◽

Callus Formation ◽

Case Series ◽

Tibial Osteotomy ◽

Tissue Stiffness ◽

Short Term ◽

Custom Made ◽

Post Operation

It is well known that mechanical stimulation promotes indirect fracture healing by triggering callus formation. We investigated the short-term response of healing tissue to mechanical stimulation to compare the changes in tissue stiffness during stimulation and resting phases in a preclinical case-series. Four sheep underwent a tibial osteotomy and were instrumented with a custom-made active fixator which applied a mechanical stimulation protocol of 1000 cycles/day, equally distributed over 12 h, followed by 12 h of rest. During each cycle, a surrogate metric for tissue stiffness was measured, enabling a continuous real-time monitoring of the healing progression. A daily stiffness increase during stimulation and an increase during resting were evaluated for each animal. One animal had to be excluded from the evaluation due to technical reasons. For all included animals, the stiffness began to increase within the second week post-op. A characteristic pattern was observed during daily measurements: the stiffness dropped considerably within the first stimulation cycles followed by a steady rise throughout the rest of the stimulation phase. However, for all included animals, the average daily stiffness increase within the first three weeks post operation was larger during resting than during stimulation (Sheep I: 16.9% vs. −5.7%; Sheep II: 14.7% vs. −1.8%; Sheep III: 8.9% vs. 1.6%). A continuous measurement of tissue stiffness together with a controlled fracture stimulation enabled the investigation of the short-term effects of specific stimulatory parameters, such as resting periods. Resting was identified as a potentially determining factor for bone healing progression. Optimizing the ratio between stimulation and resting may contribute to more robust fracture healing in the future.

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