Elsevier

Bone

Volume 81, December 2015, Pages 662-668
Bone

Original Full Length Article
Bone growth resumption following in vivo static and dynamic compression removals on rats

https://doi.org/10.1016/j.bone.2015.09.013Get rights and content

Highlights

  • Compression reduces bone growth and is used in clinical pediatric treatments to correct deformities during growth spurts

  • Bone growth resumption and mineralization were compared after static versus dynamic compressions, in vivo on the rat tail

  • Bone growth resumed after static or dynamic compression removals; rats with dynamic compression had higher mineralization

  • No neuropathic pain was induced by implanting a device nor adding static or dynamic compression within physiological ranges

  • Bone growth resumption provide evidence to support fusionless treatments of pediatric musculoskeletal deformities

Abstract

Mechanical loadings influence bone growth and are used in pediatric treatments of musculoskeletal deformities. This in vivo study aimed at evaluating the effects of static and dynamic compression application and subsequent removal on bone growth, mineralization and neuropathic pain markers in growing rats. Forty-eight immature rats (28 days old) were assigned in two groups (2- and 4 weeks experiment duration) and four subgroups: control, sham, static, and dynamic. Controls had no surgery. A micro-loading device was implanted on the 6th and 8th caudal vertebrae of shams without loading, static loading at 0.2 MPa or dynamic loading at 0.2 MPa ± 30% and 0.1 Hz. In 2-week subgroups, compression was maintained for 15 days prior to euthanasia, while in 4-week subgroups, compression was removed for 10 additional days. Growth rates, histomorphometric parameters and mineralization intensity were quantified and compared. At 2 weeks, growth rates and growth plate heights of loaded groups (static/dynamic) were significantly lower than shams (p < 0.01). However, at 4 weeks, both growth rates and growth plate heights of loaded groups were similar to shams. At 4 weeks, alizarin red intensity was significantly higher in dynamics compared to shams (p < 0.05) and controls (p < 0.01). Both static and dynamic compressions enable growth resumption after loading removal, while preserving growth plate histomorphometric integrity. However, mineralization was enhanced after dynamic loading removal only. Dynamic loading showed promising results for fusionless treatment approaches for musculoskeletal deformities.

Introduction

Mechanical loadings are essential for normal bone growth and tissue health. In growing individuals, asymmetric loading or overloading contributes to the progression of musculoskeletal deformities such as adolescent idiopathic scoliosis [1], early onset scoliosis [2], limb asymmetries [3], genu varum [4] or Blount's disease [4], [5]. Several in vivo animal studies [6], [7], [8], [9] provide evidence that compressive loading reduces bone growth rate while releasing compression accelerates it, according to the Hueter–Volkmann principle [10], [11]. Fusionless or growth friendly [2], [12] devices use the patient's remaining growth potential to apply appropriate loadings to reverse or halt the progression of the deformity [12]. In vivo studies in rats and rabbits reported bone growth rate reduction due to both static and dynamic compressions [7], [9], [13] along with decreases in growth plate height [6], [9], proliferation [6], and hypertrophic cell height as a marker of hypertrophy [9]. Studies showed that dynamic loading better preserved growth plate integrity causing fewer morphologic changes to the growth plate [9]. However, loading duration [6], [14] and magnitudes [7], [13] were found to influence growth plate function.

Upon correction of the deformity, fusionless implants need to be removed, possibly with a remaining growth potential. However, it is not known if the physis would preserve its integrity and functionality. The in vivo study by Mente et al. investigated long-term effects of static compression application and removal on bone growth and growth plate integrity, and found growth resumption in rats [11]. Dynamic loading removal was investigated by Ohashi et al. on a rat ulna model [13]. They observed recovery of longitudinal bone growth in two groups with magnitudes within physiological ranges. Animals with supra-physiological dynamic magnitude still had reduced growth, as well as greater growth plate heights, and impaired mineralization [13]. Mineralization and newly formed bone can be affected by mechanical loadings through the bone remodeling process referred to as Wolff's law [15], [16]. In growing bones, no studies report in vivo effects of physiological mechanical loading on early stages of mineralization in the hypertrophic growth plate zone and subsequently its relation to bone quality.

The in vivo rat tail model is used to study growth plate mechanobiology, through minimally invasive surgery of an external device implantation [11], [17]. However, implantation surgery may lead to central neurogenic changes, modifying nociceptive signal transmission and modulation. In particular, substance P (SP) and calcitonin gene-related peptide (CGRP) are nociceptive peptides, which play key roles in pain transmission and sensitization [18]. Both peptides can be found in the spinal cord dorsal horn [19]. Following lesions in articulations [20], [21], [22] and tendons [23], these peptide concentrations increase and are associated with pain-related behaviors in rats.

The objective of this in vivo study using the rat tail model was to assess the effects of sequential full-time loading application and removal on bone growth, more specifically growth rate, histomorphometry, mineralization and neuropathic pain. The research hypotheses stated that (1) dynamic as opposed to static compression removal restores bone growth rate, (2) static loading affects growth plate histomorphometry and mineralization, while dynamic loading preserves it, and finally (3) both static and dynamic loadings cause neuropathic pain.

Section snippets

In vivo experimental conditions

The Institutional Animal Care Committee approved the protocol. Forty-eight male Sprague–Dawley rats (28 days old) were divided into two groups by experiment duration (2-week and 4-week), each containing four subgroups: control, sham, static, and dynamic (Table 1). In 2-week groups, compression was applied full time for 15 days before euthanasia (43 days old). In 4-week groups, compression was removed for 10 additional days before euthanasia (53 days old) (Fig. 1-A, Table 1). In both 2- and 4 -week

Results

Rats had similar weight at surgery day for both 2- and 4-week groups (Table 1). At dissection, significantly lower body weight was observed between 2-week shams and controls (p = 0.019) (Table 1) but no other differences were identified in loaded groups or at 4 weeks.

No neurogenic pain is associated with surgical procedure nor loading application and removal

Pain-related peptide analysis suggested that there was no long-term neurogenic pain associated neither with the surgical procedure nor with static or dynamic compressions. Both SP and CGRP concentrations were found to be within normal ranges, similarly to control rats of other studies [20], [22].

Bone growth is modulated by both static and dynamic compression applications and removals

After 2 weeks of compression, our results are comparable to growth modulation values in the literature, confirming no differences in growth rates between static [8], [9] and dynamic compressions [9]. No

Conclusion

This study showed that growth resumption occurs following both static and dynamic (30%, 0.1 Hz) compressive loading removals at physiological levels of 0.2 MPa. Growth plate integrity was maintained in both static and dynamic cases, while mineralization discriminated between loading types as it was significantly upregulated after dynamic loading removal. Dynamic loading at 0.2 MPa and 0.1 Hz could produce a combined anabolic effect on bone growth and bone remodeling responses. This knowledge is

Acknowledgments

The authors acknowledge helpful contributions and technical skills of laboratory team members in particular Aurélie Benoit, Charlotte Zaouter, Souad Rhalmi, as well as Sainte-Justine University Hospital animal care technicians. More specifically, the authors would like to thank Rosa Kaviani for sharing her quantification program for alizarin red staining measurements. Funding for this study was provided by the Natural Sciences and Engineering Research Council of Canada (NSERC, no. 298209-2009)

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