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LIPUS: An Effective Alternate Option to Treat Nonunions of Fractures and Surgical Fusions in Trauma and Orthopaedic Surgery

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Background: Limited studies have been conducted to evaluate the use of exogen in different patient groups. We aim to determine the rate of radiological union and symptom resolution following use of Low Intensity Pulsed Ultrasound (LIPUS) therapy, to analyse the efficacy of LIPUS therapy in comparable patient groups, and to determine the cost effectiveness of LIPUS therapy. Materials and Methods: 32 adult patients with nonunions of fractures and surgical fusions who were treated with LIPUS over 3 years were identified from the clinic database. Data were recorded retrospectively. Patients were divided into 3 subcategories to provide a meaningful analysis of comparable groups: foot and ankle versus other regions, surgical versus conservative management, and atrophic versus hypertrophic nonunion. A statistical calculator was employed for statistical analysis. Results: Clinical symptoms of nonunion resolved in 19 (59%) patients and radiological union was achieved in 18 (56%) patients post LIPUS use. The foot and ankle group demonstrated the best outcome, with union rates of 73% when compared to other fractures at 44% union. Significant potential cost savings of £3150 per patient have been calculated (p=0.006) when compared to surgical management of nonunion. Discussion: Overall, we achieved just under 60% resolution of clinical symptoms and/or radiological improvement, without the need for further intervention. In our study we observed particularly better outcomes in the foot and ankle group compared to other fractures; this could provide guidance for future targeting of LIPUS therapy to specific patient cohorts based on their anatomical regions of nonunion.
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16
Archives of Orthopedics and Rheumatology V4 . I1. 2021
Introduction
The healing of bone following fractures and surgical
fusion procedures is a complex biomechanical
process[1]. Around 98% of fractures undergo primary
      
      
     


and socioeconomic burden. It also poses considerable

 
the treatm
There are several treatment options available for
      
       

     
   
potential for further complications[7]. In an attempt
      
options have emer
Archives of Orthopedics and Rheumatology
ISSN: 2639-3654 | Volume 4, Issue 1, 2021
DOI: https://doi.org/10.22259/2638-3654.0401003
LIPUS: An Effective Alternate Option to Treat Nonunions
of Fractures and Surgical Fusions in Trauma and
Orthopaedic Surgery
Maria Nowicka1, Darren Marshall2, Haroon Majeed3*
12
3

*Corresponding Author:
Haroon Majeed, 
Manchester Foundation Trust, UK.
Abstract
Background: Limited studies have been conducted to evaluate the use of exogen in different patient groups. We
aim to determine the rate of radiological union and symptom resolution following use of Low Intensity Pulsed
            
determine the cost effectiveness of LIPUS therapy.
Materials and Methods: 32 adult patients with nonunions of fractures and surgical fusions who were treated

were divided into 3 subcategories to provide a meaningful analysis of comparable groups: foot and ankle
versus other regions, surgical versus conservative management, and atrophic versus hypertrophic nonunion. A
statistical calculator was employed for statistical analysis.
Results: Clinical symptoms of nonunion resolved in 19 (59%) patients and radiological union was achieved in
18 (56%) patients post LIPUS use. The foot and ankle group demonstrated the best outcome, with union rates


Discussion:            
improvement, without the need for further intervention. In our study we observed particularly better outcomes
in the foot and ankle group compared to other fractures; this could provide guidance for future targeting of

Keywords: LIPUS; Exogen; Fracture; Nonunion
17 Archives of Orthopedics and Rheumatology V4 . I1. 2021

      
     
       
  
healing.
       
      
in micromechanical stress. This mechanical stress
transiently increases the membrane expression of


     
maturation of osteoblasts and results in endochondral

       
  

surgical fusions in trauma and orthopaedic surgery.
Material and Methods
        
       
to September      
     
     
 
      
    
      
     
       
     
     
complications following therapy or further treatments

      
     
order to provide a meaningful analysis of comparable
      
subcategories:
 
 
 
A statistical calculator was employed for statistical
analysis. Categorical data were analysed using the
     
included clinical resolution of symptoms and presence
     

 
test was used to calculate the p value. The p value

analysis.
Results
      
included in the analysis. There were 14 (44%) male
        
       
      
undergone elective joint fusion surgery. The list of

       
amongst the cohort. The average nonunion gap was
     
plain radiographs or the computed tomography (CT)
scans at the time of establishing the diagnosis of
nonunion.
LIPUS: An Effective Alternate Option to Treat Nonunions of Fractures and Surgical Fusions in Trauma
and Orthopaedic Surgery
Table1. List of diagnoses amongst patient cohort
Diagnosis Number of cases
Subtalar fusion
 
1st 1
 
 
 
 1
 
 
 
 
 
 1
18
Archives of Orthopedics and Rheumatology V4 . I1. 2021
       
resolution and demonstrated radiological union on



       
symptoms as well as radiological union following

The interval from the initial fracture or primary
surgical procedure until a diagnosis of nonunion was
suspected or established was less than 6 months in 16


was performed to evaluate the relationship between time
to diagnosis of nonunion against the average duration
      

        
persisting symptoms and no radiological progression of
union. 7 of these patients underwent revision surgery.


      
        
   
     
surgery could go ahead. The other patient refused
to undergo surgery as the residual symptoms were
       

LIPUS: An Effective Alternate Option to Treat Nonunions of Fractures and Surgical Fusions in Trauma
and Orthopaedic Surgery
The average time from injury or surgery to the time of


      

        
in their medical notes. The average duration of use of


     
         
        

        


Table2. Comparison of duration of treatment, symptom resolution, and radiological union in time to diagnosis of
nonunion groups.
Time to diagnose
nonunion
Number of cases
(%)
Average duration of
treatment in weeks
Symptom
resolution (%)
Radiological
union (%)
<6 months    
>6 to 8 months    
>9 months    
p value  
Table3. Comparison of duration of treatment, symptom resolution, and radiological union in the subgroup
analysis
Number of cases
(%)
Average duration of
Exogen used in weeks
Symptom
resolution (%)
Radiological
union (%)

nonunions
 16 11 (69) 
Other fractures  19  7 (44)
P value   
Surgical
management
14 (44)   
Conservative
management
 18 11 (61) 
P value   
Atrophic  16  
Hypertrophic  19 9 (69) 
P value   
19 Archives of Orthopedics and Rheumatology V4 . I1. 2021
LIPUS: An Effective Alternate Option to Treat Nonunions of Fractures and Surgical Fusions in Trauma
and Orthopaedic Surgery
     
       
       
         
some resolution of symptoms without any further

       
reported persisting symptoms. They both were
suspected to have developed an adverse reaction to
       
      
        



t       

  
Ten (67%) patients had atrophic nonunion. There

failed treatment group.
      
      
fusions versus other regions; fractures managed
surgically versus conservatively; and atrophic versus
    

     
      
the results of this analysis.
Table 4.
Diagnosis Initial
treatment
Revision surgery Smoking status Radiological appearances
of nonunion

comminuted fracture


  Hypertrophic
Humeral shaft fracture Conservative in

  Atrophic

fracture
   Hypertrophic
Humeral shaft fracture Humeral brace 

 Hypertrophic

fracture
   Atrophic
Humeral shaft
comminuted fracture
Humeral brace   Hypertrophic

osteoarthritis
Conservative in


fusion
 Atrophic
Fig1. Symptom resolution and radiological union in each subgroup
20
Archives of Orthopedics and Rheumatology V4 . I1. 2021
Discussion

   
demonstrates the rates of symptomatic resolution and
fracture union in the subgroups which are discussed
below in more detail.
Foot and Ankle Vs other Regions
       
      
  
regions (p      
      
radiological and symptomatic union following the
 reported a similar

rate of union in upper limb fractures compared to the

hypothesis to explain this trend considers the inherent

maintain stability of a humeral fracture and allow for
     

       
suggesting there may be an issue with the stability of

therapy.
Another contributing factor is the potential impact
    
   
         
        
the target area without any divergence of the waves.

than other regions of the body where the presence
of excessive soft tissue may potentially lower the
       




Hypertrophic vs Atrophic
        
     
      
  p   
demonstrated a greater proportion of symptom
resolution in comparison to the atrophic group (69%
p 
       
       
atrophic nonunions.

of blood vessels in comparison to normal healing
groups and may also be characterised by dysfunctional
mesenchymal stem cells at the fracture site[16].
These factors may explain relatively poor outcomes of

the hypertrophic nonunions reported in the literature.
Although in our study radiological union rates were
        
      

et al[17] who found that hypertrophic nonunions
 
      
associated with atrophic nonunion has further been
demonstrated by Watanabe et al[18]. Among a group
        
  p     
        
hypertrophic nonunion. Atrophic nonunion may
    

      
secondary to problems with mechanical instability.
        
of hypertrophic nonunions as it does not address the
underlying mechanical instability theorised to cause
a hypertrophic nonunion; further research could be
conducted to evaluate this.
Conservative vs Surgical Management
      
conservatively prior to developing nonunion and the
remainder had nonunion following their primary
surgical procedures. The conservatively managed
group showed improved radiological union rates
      
p
resolution rates were similar between the two groups
    p 
      
both such groups. Hemery et al[19] presented a 79%
success rate in a case series of 14 patients with femoral
LIPUS: An Effective Alternate Option to Treat Nonunions of Fractures and Surgical Fusions in Trauma
and Orthopaedic Surgery
21 Archives of Orthopedics and Rheumatology V4 . I1. 2021
Cost Implications
Cost analysis was performed on these patients who
     
estimates the average cost saving associated with
eliminating the need for revision surgery in those
 The

patient for the duration of its usage. This was compared
against the potential cost of revision surgery that

nonunion and the type of revision surgery that could


        
  

        
LIPUS: An Effective Alternate Option to Treat Nonunions of Fractures and Surgical Fusions in Trauma
and Orthopaedic Surgery
and tibial fracture nonunions managed surgically.
         
       
      

       
both conservatively managed and surgically managed
nonunion.
2a 2b
Fig2 (a & b). 
after the base of 5th metatarsal fracture (2a). Treated with Exogen for 4 months that led to complete resolution
of symptoms and radiological union (2b).
3a 3b 3c
Fig7 (a, b & c). 

Treated with Exogen for 4 months that led to complete resolution of clinical symptoms and radiological
progression to union (3c).
22
Archives of Orthopedics and Rheumatology V4 . I1. 2021
     
to potential surgery (p    
       
       
considered safe and has no potential complications or

Strengths and limitations
The main strength of our study is an elaborated
      
     
       
This could provide guidance for future targeting of
      
their anatomical regions of nonunion.
wledge limitations of our study. The study
  
      
       
        
     


      
   
       established
nonunions in fractures and fusion procedures in
         


to treat these patients.
References
      [1]
     

     
      
       


  
Health economics: a cost analysis of treatment
     


[4]
      
    

      
complex tibial and femoral nonunion using the



       [6]
Treatment of nonunions and osseous defects
with bone graft and calcium sulfate. Clin Orthop
   

       [7]
        
      
      
fracture nonunions: a retrospective cohort
        

[8]
      
   

       [9]
       
    
     

      
    
      

      [11]
      


     
    

 



   
i

LIPUS: An Effective Alternate Option to Treat Nonunions of Fractures and Surgical Fusions in Trauma
and Orthopaedic Surgery
23 Archives of Orthopedics and Rheumatology V4 . I1. 2021

use of low intensity pulsed ultrasound for bone


       [14]





 

[16]
     
    

[17]
       
    
  
    

       [18]
 
    
ultrasound for delayed unions and nonunions:
      


  [19]

     
     

    
    
     

     
     
     


LIPUS: An Effective Alternate Option to Treat Nonunions of Fractures and Surgical Fusions in Trauma
and Orthopaedic Surgery
Citation: Maria Nowicka, Darren Marshall, Haroon Majeed. LIPUS: An Effective Alternate Option to Treat
Nonunions of Fractures and Surgical Fusions in Trauma and Orthopaedic Surgery. Archives of Orthopedics and
. 
Copyright:   Maria Nowicka, Darren Marshall, Haroon Majeed. This is an open access article
distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Introduction: Bone fractures fail to heal and form nonunions in roughly 5% of cases, with little expectation of spontaneous healing thereafter. We present a systematic review and meta-analysis of published papers that describe nonunions treated with low-intensity pulsed ultrasound (LIPUS). Methods: Articles in PubMed, Ovid MEDLINE, CINAHL, AMED, EMBASE, Cochrane Library, and Scopus databases were searched, using an approach recommended by the Methodological Index for Non-Randomized Studies (MINORS), with a Level of Evidence rating by two reviewers independently. Studies are included here if they reported fractures older than 3 months, presented new data with a sample N≥12, and reported fracture outcome (Heal/Fail). Results: Thirteen eligible papers reporting LIPUS treatment of 1441 nonunions were evaluated. The pooled estimate of effect size for heal rate was 82% (95% CI: 77-87%), for any anatomical site and fracture age of at least 3 months, with statistical heterogeneity detected across all primary studies (Q=41.2 (df=12), p<0.001, Tau(2)=0.006, I(2)=71). With a stricter definition of nonunion as fracture age of at least 8 months duration, the pooled estimate of effect size was 84% (95% CI: 77%-91.6%; heterogeneity present: Q=21 (df=8), p<0.001, Tau(2)=0.007, I(2)=62). Hypertrophic nonunions benefitted more than biologically inactive atrophic nonunions. An interval without surgery of <6months prior to LIPUS was associated with a more favorable result. Stratification of nonunions by anatomical site revealed no statistically significant differences between upper and lower extremity long bone nonunions. Conclusions: LIPUS treatment can be an alternative to surgery for established nonunions. Given that no spontaneous healing of established nonunions is expected, and that it is challenging to test the efficacy of LIPUS for nonunion by randomized clinical trial, findings are compelling. LIPUS may be most useful in patients for whom surgery is high risk, including elderly patients at risk of delirium, or patients with dementia, extreme hypertension, extensive soft-tissue trauma, mechanical ventilation, metabolic acidosis, multiple organ failure, or coma. With an overall average success rate for LIPUS >80% this is comparable to the success of surgical treatment of non-infected nonunions.
Article
Full-text available
Background and purpose: Exogenous electromagnetic fields (EMFs) affect bone metabolism, but the mechanisms responsible for this phenomenon are unclear. Pulsed EMFs (PEMFs) can be effective in the management of congenital pseudarthrosis or delayed union or non-union of fractures. We investigated the effects of PEMFs used in clinical practice on human osteoblast cultures. Methods: Primary osteoblastic cells were isolated from a human femoral head. Cultures were exposed to the PEMF stimulation for 72 hours, 7 and 10 days and compared with a control group of primary osteoblastic cells non-exposed to PEMF. Cell growth and alkaline phosphatase activity were evaluated in the osteoblast cell cultures at each observation time. Results: At each observation time, the differences in cell numbers between PEMF-exposed cells and control group were statistically significant (p < 0.05). The alkaline phosphatase-specific activity of PEMF-exposed osteoblast cultures showed a statistically significant (p < 0.05) increase when compared with the control group after 7 and 10 days of exposure. Conclusions: The application of PEMF stimulation on human osteoblasts accelerates cellular proliferation when compared with a control group of non-PEMF-exposed cells.
Article
Full-text available
It has been shown that ultrasound (US) stimulation accelerates fracture healing in animal models and in clinical studies. Here we found that US stimulation transiently increased the surface expression of alpha2, alpha5, beta1, and beta3 integrins in cultured osteoblasts, as shown by flow cytometric analysis and immunofluorescence staining. US stimulation increased prostaglandin E(2) formation and the protein and mRNA levels of cyclooxygenase-2 (COX-2). At the mechanistic level, anti-integrin alpha5beta1 and alphavbeta3 antibodies or rhodostomin, a snake venom disintegrin, attenuated the US-induced COX-2 expression. Phosphatidylinositol 3-kinase (PI3K) inhibitors 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) and wortmannin also inhibited the potentiating action of US. US stimulation increased the phosphorylation of focal adhesion kinase (FAK), extracellular signal-regulated kinases (ERK), p85 subunit of PI3K, and serine 473 of Akt. COX-2 promoter activity was enhanced by US stimulation in cells transfected with pCOX2-Luc. Cotransfection with dominant-negative mutant of FAK(Y397F), p85(Deltap85), Akt(K179A), or ERK2(K52R) inhibited the potentiating action of US on COX-2 promoter activity. Expression of mineralized nodule was lower in dominant-negative mutants of FAK, p85, and Akt-transfected clones than in vector-transfected control cells. Taken together, our results provide evidence that US stimulation increases COX-2 expression and promotes bone formation in osteoblasts via the integrin/FAK/PI3K/Akt and ERK signaling pathway.
Article
Background: If some predictable factors that affect the treatment results of low-intensity pulsed ultrasound (LIPUS) for delayed union or nonunion could be determined, these might provide us with suggestions for whether LIPUS should be used as an alternative treatment for surgery or an adjuvant therapy after surgery. Therefore, the objective of the present study was to determine what factors affected failure of fracture healing after LIPUS for delayed unions and nonunions. Methods: A one-year observational retrospective cohort study was conducted with a consecutive cohort of 101 delayed unions and 50 nonunions after long bone fractures that were treated with LIPUS between May 1998 and April 2007. The main outcome measure was radiographic determination of osseous bone union status within one year after start of LIPUS therapy. Statistical evaluation was used to recognize predictable factors that affect treatment results of LIPUS for delayed union and nonunion. Results: Delayed union group (n = 101): Seventy-five delayed unions (74.3%) united without an additional major surgical intervention. Failure of LIPUS therapy was associated with types of nonunion (atrophic/oligotrophic vs. hypertrophic, relative risk 23.72 [95% CI 1.20-11.5], p < 0.01), instability at fracture site (unstable vs. stable, relative risk 3.03 [95% CI 1.67-5.49], p < 0.001), and maximum fracture gap size not less than 9 mm (relative risk 3.30 [95% CI 1.68-6.45]). Nonunion group (n = 50): Thirty-four nonunions (68.0%) united without an additional major surgical intervention. Failure of LIPUS therapy was associated with method of fixation (intramedullary nail vs. others, relative risk 4.50 [95% CI 1.69-12.00], p < 0.001), instability at fracture site (unstable vs. stable, relative risk 4.56 [95% CI 2.20-9.43], p < 0.0001), and maximum fracture gap size not less than 8 mm (relative risk 5.09 [95 % CI 1.65-15.67]). Conclusions: LIPUS should be applied as an adjuvant therapy in combination with surgical intervention for an established atrophic nonunion with instability and/or with larger fracture gap.
Article
Non-union is presently managed exclusively by surgery, but alternative treatments are under evaluation. To assess the benefit of external ultrasound stimulation in surgically treated lowerlimb long-bone non-union. A retrospective series of 14 patients were treated using the Exogen(®) ultrasound stimulator (Smith & Nephew Inc., Memphis, TN, USA) as part of management of surgically treated long-bone non-union. They received 20min stimulation daily over a period of 3 months. Regular clinical and radiological follow-up checked treatment efficacy. The mean interval to initiation of Exogen(®) treatment after initial surgery was 361 days (range, 6, 38 months). Bone consolidation was obtained in 11 of the 14 cases (79%), and within 3 months of initiation of Exogen(®) treatment in 27% (3/11), within 6 months in 27% (3/11) and within 9 months in 46% (5/11). There were no treatment-linked complications. There was no significant correlation between interval to initiation of ultrasound treatment and bone consolidation. Associated sepsis or atrophy did not significantly impact treatment efficacy. The reference treatment strategy in non-union is surgical revision, with consolidation rates ranging from 85 to 100% according to the series. This attitude entails risk of complications, notably infection and postoperative pain. The present results were comparable to those of the literature, with 79% bone consolidation and no complications. Ultrasound stimulation proved an effective and non-invasive treatment for non-union. Retrospective study, level IV.
Article
A shock wave is a transient pressure disturbance that propagates rapidly in three-dimensional space. It is associated with a sudden rise from ambient pressure to its maximum pressure. A significant tissue effect is cavitation consequent to the negative phase of the wave propagation. The current authors summarize the basic physics of shock waves and the physical parameters involved in assessing the amount of energy delivered to the target tissue and in comparing the various high- and low-energy devices being evaluated clinically for musculoskeletal applications.
Article
The treatment of long bone nonunions and fractures with osseous defects is challenging. The results of 26 patients with either a persistent long bone nonunion or an osseous defect after an open fracture were reviewed. Each patient was treated with debridement of devitalized tissue, open reduction and internal fixation, and bone grafting using a mixture of autogenous iliac crest bone graft and medical grade calcium sulfate. The current study evaluated the union rate and associated complications for treatment of these injuries using this protocol. Each nonunion was confirmed intraoperatively, and healing was determined clinically by the patients' return to full activities without pain and radiographically by the presence of bridging trabeculae. Complications included persistent nonunion (four patients), wound drainage (five patients), wound drainage and cellulitis (one patient) and cellulitis alone (one patient). Using this treatment protocol, 22 patients (85%) achieved healing after one surgery and an additional two patients (92%) achieved healing after a second surgery. Medical grade calcium sulfate increases the volume of graft material, facilitates bone formation, and is safe in the treatment of nonunions and fractures with osseous defects.
Article
To study the efficacy of low-intensity pulsed ultrasound (US), or LIPUS, of 85 treated nonunion cases with a minimum fracture age of 8 months, 67 cases met the study criteria. These were: no surgical intervention during 4 months before US treatment and radiographically ceased healing for 3 months before US. In a self-paired control study, the mean fracture age of the 67 patients was 39 +/- 6.2 months. After a daily 20-min US treatment at home for an average of 168 days, 85% (57 of 67) of the nonunion cases were clinically and radiographically healed. The study did not include any cases that were malaligned, grossly instable, actively infected or that had extensive bone loss. The results demonstrate that the specific US can effect heal rates similar to those achieved by surgical means, without the associated risks and complications, and to those achieved by electrical bone growth stimulation or by extracorporeal shock-wave therapy.
of non-union per fracture: current myths and revised figures from a population of over 4 million adults
  • Z Dahabreh
  • R Dimitriou
  • P V Giannoudis
of non-union per fracture: current myths and revised figures from a population of over 4 million adults. Acta Orthop 88 (4):434-439. doi :10.1080/17453674.2017.1321351 Dahabreh Z, Dimitriou R, Giannoudis PV (2007)
Health economics: a cost analysis of treatment of persistent fracture non-unions using bone morphogenetic protein-7
Health economics: a cost analysis of treatment of persistent fracture non-unions using bone morphogenetic protein-7. Injury 38 (3):371-377. doi:10.1016/j.injury.2006.08.055 Kanakaris NK, Giannoudis PV (2007) The health