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1. Introduction

Post-surgical fracture nonunion (PSFN) is defined as failure to achieve cortical continuity at the fracture site as determined by radiological examination at 6-9 months after the orthopedic operation (such as osteotomies and arthrodesis), and had a prevalence of 4.9-6.8% in patients with fracture during 2011-2019 (1,2). PSFN causes a considerable disease burden in patients with fractures, including long-term chronic pain, leading to disability and reducing the quality of life. Furthermore, it may be associated with an increased risk of death (3-6). Currently, the most commonly used treatment modalities for patients with PSFN include drug therapy (such as skeleton growth factor and teriparatide) and surgical therapy (autogenous bone grafting and internal fixation surgery), with surgical therapy being regarded as the gold standard (7-9). Although the union rate is as high as 70.4-89.2% (reported in different countries during 2011-2021) after surgical intervention, a non-negligible proportion of patients with PSFN still face post-surgical complications due to its invasiveness (10-12). Therefore, less invasive methods are needed to improve the prognosis of patients with PSFN.

Extracorporeal shock wave treatment (ESWT) is a treatment modality that converts the acoustic pulses to a shock wave, and it delivers these short and intense acoustic energy impulses into the targeted bone fracture site through skin and superficial tissues, which then convert into the kinetic energy and exert their therapeutic effect (13-15). Previous studies have reported the efficacy of ESWT in treating patients with fracture nonunion (14,15). For instance, a randomized controlled trial enrolled 126 patients with long-bone nonunions and these patients received ESWT or surgical treatment (including intramedullary nail fixation, plate fixation and combined nail and plate fixation), and this study indicated that ESWT could achieve similar union rates compared with that achieved with surgical therapy (71 vs. 74%) (14). In another study, ESWT induced a union rate of 73% in patients with fracture nonunion, which was similar to that observed in patients receiving surgical treatment (15). However, to the best of our knowledge, there are no studies that comprehensively evaluated the rationale, mechanism and implementation of ESWT in patients with PSFN, thus the present review aimed to address this issue.

2. Mechanisms of ESWT in treating patients with PSFN

Restart of the union procedure

The concept of ESWT is as follows: The acoustic pulses are converted to a shock wave by the lithotripter, and the shock wave can propagate (the propagation of the shock wave in the media may be described as the propagation of sound in the media) in all types of media (including human soft tissue and bone). However, due to the different acoustic impedance of various media, its attenuation varies. If the acoustic impedance (which may be described as the resistance faced by the shock wave during the transmission of the medium; a higher acoustic impedance is associated with a higher resistance faced by the shock wave) is different at the interface of two substances, attenuation will occur at the interface, which may convert to other energies (such as kinetic energy). When a shock wave passes through human tissues, its energy is not easily absorbed by superficial tissues (such as the fat layer and muscle), but can directly reach the bone tissue. In the process of transmission to bone tissue, acoustic energy is lost, and part of the lost acoustic energy is converted to kinetic energy, which causes bone tissue damage and may further restart the bone union procedure (16). It has been reported that ESWT can deliver a high-energy shock wave within a short life cycle (~10 msec) to the targeted bone fracture site (17), thus ESWT can affect the bone tissue without damaging the soft tissues. ESWT can cause tear and shear forces at transition sites, leading to the formation of microfractures at the targeted fracture site and dividing the bone with sclerosis into minor bone fragments (0.1-3.0 mm3). Finally, the small bone fragments can fill the fracture site, acting as an autologous bone graft (18). At the same time, local bleeding can occur at the microfracture site followed by formation of hematoma, thereby restarting the fracture trauma, aggravating inflammatory responses, releasing various inflammatory cytokines (such as IL-1β and IL-6) and recruiting osteoblasts. Consequently, the bone healing process may be restarted (19,20).

At present, two types of ESWT are commonly applied: Focused ESWT (fESWT) and radial ESWT (rESWT). The former converts the acoustic pulses to a focused acoustic pressure shock wave, creating a high-pressure spot at the targeted fracture nonunion site, while the latter produces stress waves by striking the metal applicator, affecting the targeted fracture nonunion (13). There are some differences between the fESWT and rESWT: i) fESWT can lead to a higher speed of velocity of the wave in the soft tissue, while the speed of rESWT is slower (21); ii) the pressure of f-ESWT would rise in a sharp manner during a very short period, while the pressure of r-ESWT would increase in a linear manner with a long rise time duration; and iii) the wave from fESWT is more focused on the target tissue than that of rESWT, which makes it easier to reach the lesion at depth. Therefore, fESWT is more frequently used in treating bone pathology with deep penetration; in addition, it applies high-energy shock waves and anesthesia is commonly needed (21,22). By contrast, rESWT involves mid-low-energy shock waves, which are frequently used in patients with soft tissue disease (such as carpal tunnel syndrome) (13,23) and lately for treating fracture nonunion of superficial bones (such as navicular bone and tibia) (24,25).

Promotion of osteogenesis-related growth factors

ESWT can promote fracture union via some osteogenesis-related growth factors such as bone morphogenic protein 2 (BMP-2), osteocalcin and TGF-β (26-28). For instance, an in vivo study demonstrated that ESWT could achieve improved tibia healing and fracture remodeling, and increase bone mineral density values and the bone tissue formation by regulating the VEGF, van Willebrand factor, proliferation cell nuclear antigen, BMP-2 and osteocalcin released by the osteoprogenitors (26). Another study showed that ESWT could improve mineral density, induce bone formation and increase the expression of type I collagen and osteocalcin (27). Furthermore, the ESWT has also been reported to be involved in the regulation of osteogenesis-related growth factors, such as TGF-β, which further participates in the fracture union (Fig. 1) (28).

Figure 1 Hypothetical flow diagram of ESWT in the treatment of patients with post-surgical fracture nonunion. ESWT, extracorporeal shock wave treatment; BMP-2, bone morphogenic protein 2; RANKL, receptor activator of NF-κB ligand; MSCs, mesenchymal stem cells; CXCR4, C-X-C chemokine receptor type 4; SDF-1, stromal cell derived factor-1.

Activation of osteoblasts and deactivation of osteoclasts

ESWT regulates osteoblast differentiation and maturation through several pathways, such as the TGF-β/SMAD2 signaling pathway (29), and the differentiation and maturation of the osteoblasts is reported to be associated with new bone formation and development (29,30). Furthermore, it has been reported that ESWT promotes the differentiation of chondroblasts both in vivo and in vitro, which further induces endochondral ossification and implies its potential in facilitating fracture union (31).

In addition, another study established an osteoporosis rat model and treated the rats with ESWT, finding that ESWT could suppress the osteoclast activity and further promote bone healing (32-34) (Fig. 1). During this process, the actin-bundling protein L-plastin (LPL) may serve a fundamental role. It has been reported that LPL may be regulated following the regulation effect of receptor activator of NF-κB on the PI3K/AKT/specific protein 1, and the deletion of LPL may inhibit preosteoclast fusion by regulating the formation of filopodia, which further participate in the bone union procedure (35).

Differentiation of human mesenchymal stem cells (MSCs)

Chen et al (36) demonstrated that ESWT promoted the proliferation, survival and migration of MSCs. In addition, the same study revealed that ESWT was also involved in osteogenic differentiation through several mechanisms such as: i) Enhancement of the activity of alkaline phosphatase; and ii) regulation of the expression of runt-related transcription factor-2, type I collagen, osteocalcin and osteopontin. In another study, ESWT with 0.4-mJ/mm2 energy flux density was able to double the proliferation rate of MSCs (37). At the same time, ESWT also enhanced the differentiation of MSCs into osteoblasts, which implied its potential role in promoting fracture union (37). Chen et al (38) performed an in vitro experiment in which bone marrow-derived MSCs were treated with ESWT, and found that ESWT could stimulate the proliferation and osteogenic differentiation of bone marrow-derived MSCs (Fig. 1). Further in vivo experiments in the same study revealed that seeding ESWT-treated MSCs on poly-lactic-co-glycolic acid scaffolds could induce faster bone formation with more mineral apposition inside the defect site compared with that of MSCs only (38).

Angiogenesis

Angiogenesis serves an essential role in fracture union (39,40). A recent study revealed that ESWT could increase the protein expression levels of cell angiogenesis receptor VEGFR2 and angiogenesis biomarkers (VEGF/C-X-C chemokine receptor type 4/stromal cell derived factor-1 axis) (41). Another study, which involved an in vivo mouse model with skin wounds treated with ESWT, indicated that ESWT could promote wound healing through regeneration of microcirculation and angiogenesis. In addition, a higher ESWT pulse was associated with an improved recovery effect (42). Furthermore, Modena et al (43) suggested that ESWT could activate angiogenesis by upregulating the angiogenesis markers (CD105 and VEGF) (Fig. 1).

Biomineralization

Sternecker et al (44) treated zebra mussel Dreissena polymorpha with ESWT and analyzed the biological response to evaluate the molecular mechanism of newly formed mineralized tissue after ESWT. The study found that ESWT with a 0.4 mJ/mm2 energy density could achieve an increment of bone mineralization compared with the control. This finding was further supported by a recent study that proposed a positive association between ESWT energy and the fluorescence intensity of the mineralized tissue (45). The two aforementioned studies suggested that ESWT promoted fracture union by inducing biomineralization (Fig. 1).

Others

Although there is still no definite conclusion, some studies have focused on the mechanism of ESWT on the musculoskeletal and neuromuscular system (46-48). ESWT could alter the elasticity and extensibility of the muscle, which would further benefit the bone union (49,50). However, more studies are needed for further exploration.

3. Efficacy and safety of ESWT in treating patients with PSFN

ESWT monotherapy

In 2001, Rompe et al (51) performed a study on 42 patients with PSFN who were previously treated with pseudarthroses after fracture or corrective osteotomies. All patients received fESWT with 3,000 impulses at 0.6 mJ/mm2 energy flux density for 50-75 min after local anesthesia with a bone union rate of 72.0% at 9 months after fESWT. Furthermore, Elster et al (52) re-evaluated the efficacy of fESWT in 172 patients with PSFN who underwent bone fixation (including external, internal or intramedullary fixation, casting, plaster cast, bone graft and autograft). The patients with PSFN received fESWT with a median impulse number of 4,000 at 0.38-0.40 mJ/mm2 energy flux density for 20-60 min after general or local anesthesia. The results indicated a fracture union rate of 80.2% after a mean follow-up of 4.8±4.0 months (from the first fESWT to the fracture union).

The wide application of fESWT for the treatment of patients with PSFN allowed for the efficiency of rESWT in patients with PSFN to be further recognized and revealed. In 2013, Zhang et al (53) studied 42 patients with PSFN who previously received external, internal or intramedullary fixation. The patients were treated with rESWT at different shock dosages and it was found that the rESWT with 1,000 impulses of shock waves group exhibited a fracture union rate of only 28.6%, which was lower compared with that in patients with PSFN receiving rESWT with 2,000 (85.7%) and 3,000 (78.6%) impulses of shock waves. Based on these findings, the use of an rESWT dosage of <2,000 impulses of shock waves was excluded from subsequent clinical trials. In 2017, Kertzman et al (24) reported that the rESWT with 3,000 impulses of shock waves at 0.18 mJ/mm2 energy flux density per session could achieve a fracture union rate of 72.7% at 6 months after rESWT in patients with PSFN who were previously treated with internal plates, nails or intramedullary/internal screw fixations. Furthermore, a recent case report also showed the efficacy of rESWT with 3,000 impulses of shock waves in a patient with PSFN (25). Studies reporting the efficacy of ESWT in patients with PSFN are summarized in Table I.

Table I Information on the studies reporting the efficacy of ESWT in patients with post-surgical fracture nonunion.

Table I

Information on the studies reporting the efficacy of ESWT in patients with post-surgical fracture nonunion.

A, Efficacy of ESWT monotherapy
				Treatment modality		Fracture union rate
First author/s, year	Study type	No. of cases	Previous surgery type for fracture	Intervention	Control	Intervention	Control	(Refs.)
Rompe et al, 2001	Cohort	42	Pseudarthroses after fracture or corrective osteotomies	fESWT	-	72.0% (31/43)	-	(51)
Elster et al, 2009	Cohort	172	Fixation (including external, internal or intramedullary fixation, casting, plaster cast, bone graft and autograft)	fESWT	-	80.2% (138/172)	-	(52)
Zhang et al, 2013	Cohort	42	External, internal or intramedullary fixation	rESWT with 1,000 (group 1) and 2,000 (group 2) shock dosages	rESWT with 3,000 shock dosages	Group 1, 28.6% (4/14); and group 2, 85.7% (12/14)	78.6% (11/14)	(53)
Kertzman et al, 2017	Cohort	22	Internal plates, nails and intramedullary/ internal screw fixations	rESWT	-	72.7% (16/22)	-	(24)
Yue et al, 2021	Case report	1	Intramedullary nailing	rESWT	-	100.0% (1/1)	-	(25)
B, ESWT compared with surgical treatment
				Treatment modality		Fracture union rate
First author/s, year	Study type	No. of cases	Previous surgery type for fracture	Intervention	Control	Intervention	Control	(Refs.)
Cacchio et al, 2009	RCT	126	Orthopedic operation	Group 1, fESWT with Dornier lithotripter; and group 2, fESWT with Storz lithotripter	Surgical treatment	Group 1, 70.0% (26/37); and group 2, 71.0% (27/38)	73.0% (28/38)	(14)
Huang et al, 2015	RCT	72	External, intramedullary fixation	rESWT	Autogenous bone grafting	87.2% (31/35)	93.9% (29/31)	(54)
Wu et al, 2021	RCT	65	Intramedullary nailing	fESWT	Intramedullary nailing	97.0% (32/33)	75.0% (24/32)	(16)
C, ESWT combined with other therapy compared with ESWT monotherapy
				Treatment modality		Fracture union rate
First author/s, year	Study type	No. of cases	Previous surgery type for fracture	Intervention	Control	Intervention	Control	(Refs.)
Wang et al, 2006	Cohort	42	External, internal or intramedullary fixation	fESWT with bone marrow grafting	fESWT	84.2% (16/19)	82.6% (19/23)	(55)
Jin et al, 2018	RCT	48	Open reduction and internal fixation	rESWT with autologous cell growth factor injection	rESWT	95.8% (23/24)	75.0% (18/24)	(56)

[i] ESWT, extracorporeal shock wave treatment; rESWT, radial ESWT; fESWT, focused ESWT; RCT, randomized controlled trial.

ESWT vs. surgical treatment

The aforementioned surgical treatment (including external, internal or intramedullary fixation, casting, plaster cast, bone graft and autograft) is regarded as the gold standard for the treatment of patients with PSFN (7-9). Therefore, some studies have also compared the efficacy of ESWT with that of surgical treatment in patients with PSFN (14,16,54). In a study by Cacchio et al (14), a total of 126 patients with PSFN were enrolled and treated with fESWT at 4,000 impulses of shock waves at 0.40-0.70 mJ/mm2 energy flux density or with surgical treatment. A fracture union rate of 70-71% was reported in the fESWT group, which was similar to that in the surgical treatment group (73%) (14). Huang et al (54) compared the efficacy of rESWT with that of autogenous bone grafting in patients with PSFN and showed that three sessions of rESWT (3,000 impulses at 80-120 J) with 7-day intervals could achieve a fracture union rate of 87.2%, which was similar to the fracture union rate recorded in patients with PSFN receiving autogenous bone grafting (93.9%).

Furthermore, another study applied a more intensive ESWT method and compared the efficacy of this intensive method with that of surgical treatment in patients with PSFN (16). In detail, a total of 65 patients with PSFN who were previously treated with open reduction and internal fixation were enrolled. fESWT or intramedullary nailing were applied in patients with PSFN. In the fESWT group, all patients received three courses of fESWT. At each course, these patients received the fESWT for 10 min each, twice a week, for up to 4 weeks. The patients in the surgical group received the normal intramedullary nailing surgical treatment instead. The study found that the fracture union rate could increase to 97.0% in the fESWT group, which was higher compared with that in the surgical group (75.0%) (16) (Table I).

ESWT combined with other treatment modalities

Wang et al (55) compared the efficacy of fESWT combined with bone marrow grafting with fESWT alone in 42 patients with PSFN previously treated with external, internal or intramedullary fixation. fESWT with 2,000 impulses plus the autologous bone marrow grafting could achieve a fracture union rate of 84.2%, which was numerically but not statistically significantly higher compared with that in patients with PSFN receiving fESWT monotherapy (82.6%). Jin et al (56) determined the efficacy of rESWT with autologous cell growth factor injection. rESWT with 3,000 impulses and 0.54 mJ/mm2 energy flux density plus autologous cell growth factor injection could achieve a fracture union rate of 95.8%, which was higher compared with that in the rESWT group (75.0%) (Table I).

Safety

The safety profile of ESWT in patients with PSFN is generally considered acceptable (14,16,24,51,54). The most common adverse events (AEs) include skin- and blood-related AEs such as local edema, subcutaneous hematoma and peripheral blood vessel damage (14,16,24,51,54). Only a minor proportion of patients report pain (24). In addition to the common AEs, certain patients with PSFN may suffer from infection, blisters and skin ulceration (16,54). The safety profile of ESWT in PSFN is summarized in Table II.

Table II Safety profile of ESWT in patients with post-surgical fracture nonunion.

Table II

Safety profile of ESWT in patients with post-surgical fracture nonunion.

First author/s, year	ESWT type	Common AEs	(Refs.)
Rompe et al, 2001	fESWT	Transient local hematoma	(51)
Elster et al, 2009	fESWT	Dose-related local edema, cutaneous petechial hemorrhage and subcutaneous hematoma	(52)
Zhang et al, 2013	rESWT	N/R	(53)
Kertzman et al, 2017	rESWT	Pain	(24)
Yue et al, 2021	rESWT	None	(25)
Cacchio et al, 2009	fESWT	Hematomas	(14)
Huang et al, 2015	rESWT	Local edema, subcutaneous hematoma and blisters	(54)
Wu et al, 2021	fESWT	Local edema, infection, skin ulceration, peripheral blood vessel damage and peripheral nerve damage	(16)
Wang et al, 2006	fESWT	None	(55)
Jin et al, 2018	rESWT	N/R	(56)

[i] AEs, adverse events; ESWT, extracorporeal shock wave treatment; rESWT, radial ESWT; fESWT, focused ESWT; N/R, not reported.

4. Prognostic factors for patients with PSFN

Prognostic factors of fracture union in PSFN

Certain studies have explored the predictive factors for fracture union in patients with PSFN receiving secondary surgery (57-61). These prognostic factors mainly focused on demographic characteristics (such as tobacco usage) and the recovery status of the fracture nonunion (including the dislocation distance, nonunion site and the occurrence of callus in the cortex) (57-61). In a study by Gvozdenovic et al (57), patients with PSFN and minor dislocation (vs. those PSFN with greater dislocation) at the union site exhibited a higher fracture union rate after the second surgical treatment. In a study by Konda et al (59), lower extremity nonunion, tobacco use, worker's compensation insurance (which is associated with longer time to return to work and worse functional outcomes following the surgery), radiographic bone loss and preoperative short musculoskeletal function assessment function index were associated with fracture nonunion in patients with PSFN. In patients with PSFN and femoral neck nonunion, the predictive factors for revision surgery included a higher preoperative neck shortening ratio (60). In a study by Christiano et al (61), the presentation of the callus and the invisible fracture line in the cortex could also predict fracture nonunion.

A recent study established a model based on contrast-enhanced ultrasound that was applied to predict the union rate for patients with PSFN. The study showed that the peak enhancement, wash-in area under the curve (defined as the integral of the signal intensity over time until peak enhancement is reached) and wash-in perfusion index (defined as the ratio of wash-in area under the curve to rise time) at the nonunion site were increased in patients with PSFN and fracture union compared with those in patients with PSFN and fracture nonunion (60).

Prognostic factors of ESWT in treating fracture union in PSFN

Although only a small number of studies have reported the predictive factors for fracture union in patients with PSFN receiving ESWT, previous evidence has revealed that the shock wave treatment (vs. no treatment) was associated with an increased union rate in patients with PSFN (24,52,62). In addition, a shorter time between fracture and first shock wave treatment, a shorter interval between the fracture and the surgery, a good intramedullary stabilization, and an increased number of extracorporeal shock wave therapy treatments were associated with a higher fracture union rate (24,52,62).

5. Prospects and limitations

Apart from ESWT, several studies have reported advances of the treatment in bone regeneration, such as bone organoid, physical and chemical crosslinked hydrogels, polyether-ether-ketone (PEEK) and double-network metallopolymer hydrogels (63-66). For instance, one study reported that the bone organoid was constructed in vitro, which could simulate the biological function of organs in vivo, and a potential strategy for the construction of bone organoids and their application in bone reconstruction was described (63). Another study clarified that biomimetic hydrogels with injectability and compatibility may serve an essential role in bone defect reconstruction, benefiting from their numerous advantages, such as extensive selectivity, rapid gel-forming capacity, tunable mechanical properties and good biocompatibility (64).

However, several challenges should be considered before the aforemetioned advances of the treatment's broad application, such as the poor bonding of PEEK with bone and soft tissue (65). In terms of the ESWT, several limitations should also be noted: i) ESWT has a dose-dependent efficacy but an excessive dose would lead to excessive damage, while an insufficient dose would not reach the optimal efficacy, thus finding the optimal dose is a critical issue that clinicians should consider (53); ii) its effect on other tissues and organs should be studied more extensively; and iii) the construction of ESWT equipment deserves further study. Hence, for the more wide application of these advance methods (including the ESWT) in the treatment of PSFN, more studies are still needed.

6. Summary

Previous studies have reported that ESWT is able to promote fracture union in patients with PSFN (14,16,54). However, to the best of our knowledge, none of these studies comprehensively evaluated the mechanism, implementation and prognostic factors of ESWT in patients with PSFN. The present review aimed to clarify the potential mechanism for ESWT in promoting the fracture union, which mainly includes: i) Restart of the bone union process; ii) activation of osteoblasts and suppression of osteoclasts by elevating osteogenesis-related growth factors, such as BMP-2 and TGF-β, promoting several pathways, such as the TGF-β/SMAD2 signaling pathway, and inducing the differentiation of human MSCs into osteoblasts; iii) promotion of angiogenesis; and iv) biomineralization induction. The present review summarizes the efficacy and safety of ESWT in patients with PSFN, showing that ESWT was effective and tolerable. Furthermore, the current review considered the potential prognostic factors for the facture nonunion and efficacy of ESWT in patients with PSFN, which mainly included demographic characteristics, such as tobacco usage, recovery status of the fracture nonunion, time interval between fracture and first shock wave treatment or surgery, and intramedullary stabilization status. These findings could provide a theoretical basis for orthopedics specialists to improve individualized treatments and the application of ESWT in clinical practice for patients with PSFN. Further high-quality studies are required to validate these findings.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

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Authors' contributions

HW contributed to the study conception and design. HW and YS drafted and revised the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References