Bone Growth Stimulators to Enhance Spinal Fusion Outcomes

Abstract

Bone growth stimulators serve as a critical adjunct in spinal-fusion procedures, particularly in patients at risk of nonunion or delayed healing. This review analyzes three primary modalities: biological, electrical, and ultrasound-based stimulators. Biological stimulators, including bone morphogenic proteins and platelet-rich plasma, use growth factors to promote osteogenesis but carry risks such as ectopic bone formation and inflammatory responses. Electrical stimulators, such as direct current stimulation and pulsed electromagnetic fields, leverage the piezoelectric properties of bone to activate osteogenic pathways and have indicated significant efficacy in promoting fusion in high-risk populations. Low-intensity pulsed ultrasound offers a noninvasive alternative that accelerates bone healing through mechanical and angiogenic pathways. The review also evaluates the preclinical application of bone growth stimulators in animal models, exploring the integration of advanced biomaterials to further enhance osteogenesis. Future research should prioritize optimizing the efficacy, safety, and cost-effectiveness of these modalities to improve spinal-fusion outcomes.

Introduction

Bone fusion (arthrodesis) unites bones to reduce pain and is most commonly performed for spinal, ankle, and wrist conditions^1-4). These procedures typically involve grafting, with the iliac crest bone graft serving as the standard of care⁵⁾. Bone grafts must support osteoconduction (scaffolding), osteoinduction (stimulating osteoblasts), and osteogenesis (forming new bone)⁶⁾. Osteogenesis is the formation of new bone tissue⁶⁾.

Although spinal fusion relieves pain and improves function, increased use in older populations has raised concern over complications such as persistent spinal pain syndrome, which affects 5.4% of patients with lumbar fusion and contributes to substantial health care costs^7-11). This highlights the need for improved fusion techniques and outcomes.

Bone growth stimulators, including biological, electrical, and ultrasound-based options, can enhance fusion outcomes. Biological stimulators such as bone morphogenic proteins (BMPs), platelet-rich plasma (PRP), and stem cell therapies promote osteogenesis and reduce revision rates^12-14). Electrical techniques such as direct current stimulation (DCS), pulsed electromagnetic fields (PEMF), and capacitive coupling leverage bone's piezoelectric properties to support healing¹⁵⁾. Low-intensity pulsed ultrasound (LIPUS) promotes bone growth by modulating cellular proliferation and gene expression¹⁶⁾. This review summarizes molecular mechanisms, clinical outcomes, and emerging technologies shaping the future of bone growth stimulation.

Bone Morphogenetic Proteins

BMPs are growth factors that belong to the transforming growth factor beta (TGF-β) family. They play an important role in the formation and development of various tissues in the body, including bone and cartilage. The osteoinductive properties of BMPs were originally identified by their capacity to induce ectopic bone growth¹⁷⁾. Although there are more than 20 known human BMPs, only recombinant human BMP-2 (rhBMP-2) and recombinant human BMP-7 (rhBMP-7) are Food and Drug Administration (FDA) approved for commercial use. rhMBP-2 is approved for use in three indicated procedures: anterior lumbar interbody fusion (ALIF), open tibial fracture reconstruction, and maxillofacial procedures^18-20). The application of BMP-7 is much more limited, only being approved for use in revision posterolateral lumbar fusion for cases in which autograft is not an option²¹⁾.

BMPs stimulate bone growth by triggering mesenchymal stem cells (MSCs) to differentiate into osteoblasts. Although there are multiple cellular pathways in which this occurs, the Smad pathway is the most extensively studied²²⁾. Specifically, BMP-2 binds to BMP receptor types 1 and 2 on the surface of the stem cell. The binding triggers receptor type 2 to phosphorylate receptor type 1, which subsequently phosphorylates R-Smad signaling proteins Smad 1, 5, and 8. The phosphorylated R-Smads bind to Smad4, forming a complex that moves into the nucleus and regulates expression of genes responsible for bone formation, such as the Runx2 gene¹⁸⁾.

However, the cellular impacts of BMP-2 are not limited to osteoblast differentiation. For example, BMP-2 can activate the expression of genes responsible for inflammatory cytokines, leading to inflammation at surgical sites. Furthermore, BMP-2 can induce adipogenesis by way of peroxisome proliferator-activated receptor-γ signaling. BMP-2 can even induce osteoclast activity, potentially leading to complications such as osteolytic cystic lesions and bone graft subsidence¹⁸⁾.

BMPs have been the most widely used biologic stimulators in spinal fusion since their FDA approval in 2002 owing to their strong efficacy in bone healing. Randomized controlled trials of rhBMP-2 in ALIF and other lumbar fusion procedures have shown significantly higher fusion rates than has autograft (94.5% vs 88.7%), along with shorter operative times and reduced intraoperative blood loss^23,24). Observational studies support these findings and highlight the added benefit of eliminating iliac crest donor-site morbidity, which can lead to infection, chronic pain, and patient dissatisfaction²⁵⁾. Despite these advantages, complications have been reported, including ectopic bone growth, cervical spine swelling, and graft subsidence. Ectopic bone formation occurs in approximately 70% of patients with rhBMP-2 compared with 13% of controls, with postoperative radiculitis due to nerve root compression developing in 14%. Cervical use is contraindicated owing to reports of severe swelling leading to airway compromise, sometimes necessitating reoperation^18,24). At the fusion site, rhBMP-2 may induce osteoclast activity, causing graft subsidence¹⁸⁾. Additional risks include osteolysis and a potential malignancy signal, although this association remains controversial^18,24). Nevertheless, BMPs remain the most widely used biologic adjunct for lumbar fusion, given their consistently high rates of fusion success often outweigh the potential risks.

Cost-effectiveness considerations

Although rhBMP-2 is costly, ranging from $900 to $1,500 per procedure, evidence suggests that these upfront costs are offset by improved fusion success (decreasing the need for revision surgery), shortened operative times, and avoidance of iliac crest graft complications^18,26). McGrath et al.²⁶⁾ found that when surgeons were aware of rhBMP-2 costs, they used it more selectively, which reduced complication rates and overall hospital expenditures. These findings suggest that rhBMP-2 is cost-effective in carefully chosen patients at high risk, such as those prone to pseudoarthrosis.

PRP

PRP is an autologous blood product that contains platelet concentrations approximately 3-10 times higher than normal physiological levels. Activated platelets in PRP release numerous growth factors that induce bone growth, angiogenesis, and tissue healing²⁷⁾. PRP is commonly used to enhance fusion rates and reduce inflammation in numerous spinal-fusion procedures such as TLIF, lumbar posterolateral fusion, and TIF²⁸⁾.

PRP is classified by several characteristics, including leukocyte concentration (poor or rich), platelet concentration, and activation method²⁹⁾. Two common PRP production methods include the PRP method and the buffy-coat method, both of which involve differential centrifugation.

PRP enhances bone healing by releasing growth factors that induce angiogenesis, osteoblast differentiation, collagen production, and cell proliferation. The major growth factors released by activated PRP platelets include platelet-derived growth factor (PDGF), TGF-β, and insulin-like growth factor 1 (IGF-1). PDGF stimulates angiogenesis, which speeds up the healing process by increasing oxygen and nutrient supply to damaged tissue. TGF-β is a particularly important regenerative component of PRP because it has the capacity to trigger the differentiation of MSCs into bone-forming osteoblasts, predominantly through the Smad pathway^18,30). IGF-1 increases synthesis of type 1 collagen³¹⁾. Combined, these growth factors work synergistically to enhance bone healing at surgical sites³⁰⁾.

Research on the efficacy of PRP in bone fusion procedures is mixed. Some studies suggest that PRP does promote healing, whereas other studies suggest it is ineffective. For example, a study by Kubota et al.³²⁾ (2018) found that fusion rates in TLIF procedures were significantly higher with PRP than in controls (91% vs 77%). Conversely, a systematic review by Muthu et al.³³⁾ (2022) found that PRP was not significantly associated with improved postoperative pain scores, and that PRP was actually associated with lower fusion rates in spinal-fusion procedures. However, a major issue with PRP research findings is that PRP preparation and composition is not standardized, making it difficult to determine its true efficacy in clinical practice^34,35).

Spinal-fusion Clinical Evidence

Research on the efficacy of PRP in spinal fusion is mixed. For example, Kubota et al.³²⁾ (2018) reported higher fusion rates in TLIF with PRP than in controls (≈91% vs 77%). Conversely, a systematic review by Muthu et al.³³⁾ (2022) found PRP was not associated with improved postoperative pain and when pooling spinal-fusion studies, was associated with lower fusion rates. PRP has been explored as an adjunct or alternative to BMPs, but effects appear procedure- and contact-dependent, and findings vary across studies.

·[Randomized controlled trial] Kubota et al.^13,32) (TLIF): PRP increased fusion vs control (≈91% vs 77%); results vary across publications and preparation details.

·[Observational] Noguchi et al.³⁶⁾ (lateral interbody fusion with artificial bone): fusion 43% with PRP vs 26.1%without; benefit concentrated in good-contact cases, with limited effect in poor-contact scenarios.

·[Systematic reviews/meta-analyses] Multiple overviews report inconsistent PRP effects on fusion and pain, likely driven by heterogeneity in preparation/composition; several conclude no routine role^28,33,37).

Evidence synthesis: Given heterogeneous preparations and inconsistent outcomes, current evidence does not support routine PRP use for spinal fusion; recent reviews (e.g., Cai et al.³⁷⁾) find no clinical advantage and unfavorable cost-effectiveness^33,37).

Preparation Variability and Reporting

PRP efficacy signals are confounded by non-standardized preparation (e.g., leukocyte-rich vs leukocyte-poor, platelet fold-increase, activation method, single- vs double-spin). To improve interpretability, PRP class (LR-PRP vs LP-PRP), leukocyte content, platelet concentration/fold-increase from baseline, activation agent (or none), centrifugation method (PRP vs buffy-coat; single vs double-spin), and final volume/site of application should be explicitly reported^29,34,35).

Stem Cell Therapies

MSCs are a specific kind of cell that can differentiate into various cell types, including osteoblasts and chondroblasts³⁸⁾. MSCs are most commonly harvested from bone marrow, adipose tissue, and other connective tissue sources³⁹⁾. The differentiation of MSCs into osteoblasts promotes bone regeneration in numerous spinal-fusion procedures, serving as an autograft alternative⁴⁰⁾.

MSC-rich bone marrow for spinal-fusion procedures is most frequently sourced from the patient's own iliac crest to minimize immune rejection risk. However, it can also be sourced from adipose tissue through liposuction to minimize invasiveness and pain⁴⁰⁾. Once the marrow is collected, it is centrifuged to separate the MSCs from the red blood cells and plasma. The cells are often cultured in an osteogenic media for several weeks to increase cell numbers⁴¹⁾. Next, the MSCs are treated with growth factors such as rhBMP-2 or vascular endothelial growth factor (VEGF) to prime them for differentiation⁴²⁾. rhBMP-2 induces osteoblast differentiation by way of the Smad pathway, activating expression of genes such as Runx2¹⁸⁾. VEGF induces differentiation indirectly by stimulating endothelial cells to release prostanoids, subsequently stimulating osteoblast differentiation⁴³⁾. Then, an osteogenic graft scaffold is developed, often comprising natural materials such as nano-hydroxyapatite (n-Hap). Hydroxyapatite is frequently used as a scaffold material owing to its structural and compositional similarity to bone, granting it osteoinductive properties. The scaffold provides structural support for the newly developing bone and encourages osteoblast proliferation⁴²⁾. Once primed, the cells are seeded onto the scaffold to ensure uniform distribution⁴⁴⁾. The seeded scaffold is placed in interbody cages for TLIF procedures and in posterolateral gutters for Posterolateral Lumbar Fusion (PLF) procedures^45,46). Postoperatively, MSCs follow developmental stages similar to those of natural bone growth, including proliferation, matrix deposition, mineralization, and maturation⁴⁷⁾. Successful differentiation of MSCs at the operation site is characterized by bridging of bone between fusion surfaces, as indicated by postoperative computed tomography or X-ray scans⁴⁶⁾.

Owing to numerous differences across research studies regarding use of growth factors, scaffold type, and harvesting method, it is difficult to gauge the true efficacy of MSCs in spinal-fusion procedures. A systematic review by Stephan et al.⁴⁰⁾ found across multiple clinical studies that MSC fusion rates ranged from 63% to 100%, which is comparable with autograft controls. Although fusion rates are comparable, MSC-seeded scaffolds eliminate the need for iliac crest autograft harvesting, preventing complications such as loss of blood, postoperative pain, and infection. However, use of MSCs is associated with risks such as ectopic bone formation (when used with BMPs) and pain from MSC bone marrow harvesting^18,40). Off-label use of MSCs in conjunction with rhBMP-2 in cervical spinal fusions puts patients at an elevated risk for ectopic bone growth that can lead to dysphagia and life-threatening airway compromise. Consequently, compliance with FDA regulations is critical to minimize complications associated with use of MSCs in bone fusion procedures¹⁸⁾. Overall, more standardized research must be conducted to obtain a clearer picture of optimal MSC use in spinal-fusion procedures.

Spinal-fusion Evidence―Human

Across clinical studies summarized by Stephan et al.⁴⁰⁾ (systematic review), MSC-augmented lumbar/cervical fusions report ~63% to 100% fusion rates, generally comparable to autograft while avoiding iliac crest donor-site morbidity; however, designs are heterogeneous and often small. Larger, well-controlled trials are needed before routine use can be recommended⁴⁰⁾. Spine-focused reviews similarly note limited high-quality clinical evidence and substantial variability in cell source (e.g., bone marrow vs adipose), processing/priming, and scaffold selection^48,49).

Spinal-fusion Evidence―Preclinical

Preclinical studies indicate the osteogenic potential of MSCs and MSC-seeded scaffolds (e.g., n-Hap composites), with enhanced proliferation, matrix deposition, mineralization, and synergy with bioactive factors. Translation to reliable human fusion gains remains inconclusive, pending standardization of harvesting, expansion/priming, dose, and scaffold protocols^42,44,47).

Evidence Limitations and Regulatory Considerations

Outcomes vary with cell source, dose, scaffold, and growth-factor priming. Although MSC augmentation may reduce donor-site morbidity versus iliac crest autograft, risks include ectopic/heterotopic bone―especially when combined with rhBMP-2―and procedure-specific complications. Adherence to FDA guidance for human cells, tissues, and cellular and tissue-based products and avoidance of high-risk off-label cervical rhBMP-2 applications associated with dysphagia/airway events are recommended^18,40).

Clinical implications: Current human evidence supports MSC augmentation as an investigational adjunct with outcomes comparable to autograft in small, heterogeneous studies; routine use is not yet supported outside controlled indications or trials^40,48,49).

Electrical Stimulation for Bone Fusion

Electrical bone growth stimulators harness the bone's natural response to electrical signals to promote healing and enhance spinal fusion. These therapeutic devices work by imitating or amplifying endogenous bioelectrical activity, which plays an important role in fracture repair and osteogenesis⁵⁰⁾. The three most widely studied modalities are DCS, PEMF, and capacitive coupling (CC), each of which exerts osteogenic effects through distinct biophysical mechanisms.

DCS delivers a constant low-amplitude current through implanted cathodes to stimulate osteoblast differentiation and extracellular matrix deposition⁵¹⁾. PEMF uses time-varying magnetic fields to activate osteogenic signaling pathways such as Wnt/β-catenin, enhancing osteoblast proliferation and angiogenesis⁵²⁾. Meanwhile, CC applies an alternating electrical field across the fusion site, inducing calcium influx and stimulating the expression of BMPs and TGF-β⁵³⁾. These modalities have been integrated into orthopedic and spinal surgery protocols as adjuncts to improve fusion outcomes, with clinical studies showing their efficacy in accelerating bone healing and increasing fusion rates^54,55). The later sections explore these electrical stimulation techniques' molecular mechanisms and clinical applications, evaluating their role in modern orthopedic practice.

DCS

DCS involves surgically implanted cathodes delivering a constant low amperage current at the fusion site. The localized direct current (DC) field produces electrochemical changes that promote osteogenesis. For example, cathodal stimulation creates a more alkaline, low-oxygen environment that increases osteoblast activity and extracellular matrix production―studies have observed enhanced proteoglycan and collagen synthesis under DCS⁵⁶⁾. At the cellular level, DCS can upregulate key osteogenic regulators. In vitro experiments show increased expression of BMPs, including BMP-2 and BMP-7, in bone cells exposed to specific DC electric fields⁵¹⁾. DCS has also been reported to elevate osteogenic transcription factors such as Runx2 and stimulate collagen type I production, further driving osteoblast differentiation⁵⁷⁾.

Clinically, DCS has been applied as an adjunct in spinal fusion with positive outcomes. Multiple studies report higher fusion rates when using implanted DC stimulators. In patients with lumbar fusion, DCS treatment significantly improves the likelihood of achieving a solid arthrodesis compared with no stimulation⁵⁸⁾. A meta-analysis of randomized trials found that electrical stimulators―including DCS―more than doubled the odds of successful spinal fusion⁵⁴⁾. Notably, Jenis et al.⁵⁹⁾ observed instrumented lumbar fusion showed comparable efficacy of DCS and PEMF therapy, both yielding better fusion outcomes than in controls. Overall, the evidence supports that DCS enhances spinal-fusion success, particularly in high-risk or revision cases, by activating bone-forming pathways and improving the biological environment for fusion⁵⁵⁾. DCS, as an invasive modality, provides a direct osteogenic stimulus by upregulating BMPs, collagen synthesis, and key transcription factors such as Runx2, thereby improving spinal fusion rates, particularly in patients at high risk^56,58).

PEMFs

PEMF uses time-varying magnetic fields noninvasively to induce electric currents in bone tissue. These pulsed fields trigger multiple signaling cascades important for bone healing. A well-documented mechanism is activation of the Wnt/β-catenin pathway, which drives osteoblast maturation. Research indicates that PEMF exposure increases nuclear β-catenin and upregulates Wnt-related proteins in osteoblasts, thereby promoting osteogenic gene expression⁵⁰⁾. In both cell and animal models, PEMF has been shown to elevate mRNAs and proteins for Runx2, osteocalcin (OCN), and BMP-2, indicating robust stimulation of the bone formation program⁵⁰⁾.

PEMF also exerts pro-angiogenic effects that support bone regeneration. It can upregulate angiogenic factors and signaling―for instance, Delle Monache et al.⁵²⁾ note that PEMF stimulates endothelial cells and can increase the activity of VEGF pathways, enhancing new vessel formation in healing bone. Although the exact mediator can vary (fibroblast growth factor 2 has also been implicated as a key factor), the net effect is improved blood supply to the repair site, which is critical for fracture healing. Moreover, PEMF-treated osteoblasts show greater production of late-stage differentiation markers such as OCN and mineralized matrix, reflecting more complete maturation⁵⁰⁾.

Clinically, PEMF has revealed efficacy in promoting fracture union and spinal fusion. In a classic double-blind trial on delayed tibial fractures, PEMF stimulation significantly increased healing rates compared with placebo⁶⁰⁾. Similarly, in patients with spinal fusion, adjunctive PEMF therapy is associated with higher fusion success, even in those with risk factors for nonunion. A systematic review of postoperative PEMF found improved fusion outcomes and reduced pseudarthrosis rates relative to controls⁵⁴⁾. Modern prospective studies in high-risk lumbar fusion cases report fusion rates of approximately 85%-90% with PEMF, highlighting its clinical benefit in enhancing bone healing⁶¹⁾. These results reinforce that PEMF stimulation of osteogenic and angiogenic pathways translates into improved healing of fractures and spinal fusions⁵⁶⁾. DCS, as an invasive modality, provides a direct osteogenic stimulus by upregulating BMPs, collagen synthesis, and key transcription factors such as Runx2, thereby improving spinal-fusion rates, particularly in patients at high risk^56,58).

Capacitive Coupling

CC delivers an oscillating electric field between surface electrodes placed across the target bone. This alternating current field causes charge displacement in the tissue, which in turn activates voltage-gated calcium channels on bone cells. The influx of Ca²⁺ through these channels is an early step in CC's mechanism of action⁶²⁾. Blocking voltage-gated calcium channels (VGCCs) (e.g., with verapamil) has been shown to abolish the proliferative response to CC, confirming Ca²⁺ entry is critical⁶²⁾. The elevated intracellular Ca²⁺ triggers a cascade: it activates calcium-sensitive enzymes such as phospholipase A₂, increases production of secondary messengers (prostaglandin E₂), and elevates calmodulin activity in osteoblasts⁴⁸⁾. Through this pathway, CC stimulation leads to increased cell proliferation and upregulation of growth-factor genes. Notably, osteoblasts exposed to capacitively coupled fields show significantly higher mRNA levels of BMP-2, BMP-7, and other osteogenic growth factors, along with increased TGF-β1 expression⁵¹⁾. This boost in BMP-2/7 can synergistically enhance osteoblast differentiation and matrix production, contributing to a more robust fusion mass.

The net effect of CC is an acceleration of osteoblast proliferation and bone formation. Griffin et al.⁵⁵⁾ observed greater DNA synthesis and alkaline phosphatase activity in osteoblast cultures under CC stimulation, indicating enhanced proliferation and early differentiation in vitro. Over time, CC-stimulated bone cells lay down more collagen and mineralized matrix, reflecting improved osteogenesis. Clinically, CC is a proved adjunct for spinal fusion. Goodwin et al.⁶³⁾ noted that in patients with lumbar fusion, a significantly higher fusion success rate was achieved in those using CC bone stimulators (approximately 85% vs 65% in controls). These outcomes were especially pronounced in multilevel fusions with instrumentation. Subsequent clinical series and meta-analyses corroborate that CC stimulation can improve fusion rates in the lumbar spine, with efficacy comparable to that of other stimulators⁵⁴⁾. By triggering calcium-related signals and increasing bone-growing proteins such as BMP-2 and BMP-7, CC devices help create better conditions for bone healing and have been proved effective in improving spinal fusion⁵⁵⁾. CC, as a noninvasive modality, capitalizes on VGCCs to stimulate osteogenic growth factors and enhance bone matrix deposition, with clinical studies revealing significantly higher fusion rates in patients treated than in controls^55,63).

Although electrical stimulators offer numerous potential benefits to fusion outcomes, cost-effectiveness must be evaluated. For instance, procedure cost is significantly lower for patients who receive DCS with no instrumentation than for patients who did not receive DCS⁶⁴⁾. Conversely, PEMF appears to have low cost-effectiveness. For example, for scaphoid bone fractures, PEMF is more costly to use than are standard treatment methods, and equally effective⁶⁵⁾. Overall, more research must be conducted to further understand the cost-effectiveness of each method.

The Figure 1 flowchart compares three electrical stimulation modalities―DCS, PEMF, and CC―used to enhance bone fusion. DCS delivers DC to upregulate BMPs and RUNX2, promoting osteoblast differentiation and collagen synthesis. PEMF generates magnetic fields that activate the Wnt/β-catenin pathway, boosting angiogenesis and osteogenesis. CC applies alternating electric fields to stimulate VGCCs, increasing calcium influx and BMP expression to enhance bone formation.

Figure 1.

Mechanical waves stimulating the growth increase of PAK, COX-2, and PGE2, allowing an increase in both osteoblasts and osteoclasts.

Flowchart comparing three primary types of electrical stimulation used in spinal fusion: Direct current stimulation (DCS), pulsed electromagnetic fields (PEMF), and capacitive coupling (CC). Each modality exhibits a distinct mechanism of action—DCS promotes bone morphogenic protein (BMP) and RUNX2 expression; PEMF activates Wnt/β-catenin signaling and angiogenesis, whereas CC stimulates voltage-gated calcium channel-mediated calcium influx and BMP production. All modalities contribute to enhanced osteogenesis and improved clinical spinal fusion outcomes.

LIPUS

LIPUS is a noninvasive bone stimulation therapy that uses low-intensity waves to speed up bone fracture healing. Approved by the FDA in 1994, LIPUS is primarily used to treat non-unions and delayed unions^66,67). Although not fully understood, LIPUS mechanisms have been studied in preclinical models.

LIPUS promotes mechanical stimulation during the healing process, which stimulates cell signaling and physiological pathways, accelerating bone healing. Bone healing occurs in three phases: inflammatory, reparative, and remodeling. Ultrasound waves (~30 mW/cm²) convert mechanical stress into intracellular signaling. This activates focal adhesion kinase, upregulating COX-2 and prostaglandin E2, which drive inflammation and early healing (Figure 2)^67-69).

Figure 2.

Molecular mechanisms of low-intensity pulsed ultrasound (LIPUS) on bone healing.

Schematic representation of the cellular signaling cascades activated by LIPUS at a bone fracture site. Mechanical waves stimulate focal adhesion kinase, which upregulates COX-2 and increases prostaglandin E2 (PGE2) production. This cascade enhances osteoblast and osteoclast activity, promoting bone remodeling and fusion. LIPUS-induced mechanical stimulation contributes to early inflammation, cellular proliferation, and matrix formation at the fusion site.

LIPUS also promotes vascularization and angiogenesis, which are essential during the reparative phase of bone healing. Angiogenesis is the formation of new blood vessels, and Palanisamy et al.⁶⁷⁾ found that LIPUS increased the expression of mRNA responsible for angiogenesis. LIPUS stimulates VEGF-mediated angiogenesis, supporting bone regeneration⁶⁷⁾. Cavitation and acoustic streaming improve nutrient flow, permeability, and chondroblast activity, accelerating callus formation⁶⁹⁾. Clinical studies show LIPUS achieves healing rates of 82%-91% in various nonunion fracture types (Table 1)^66,68,70).

Table 1.

Comparative Summary of Bone Growth Stimulators: Mechanisms, Benefits, and Limitations.

This table provides a consolidated overview of various bone growth stimulators used in spinal fusion and fracture healing, including biological, electrical, and ultrasound-based modalities. It outlines the major advantages and disadvantages of each technique, offering a clinical perspective on their efficacy, safety, and practicality. Bone morphogenetic proteins (BMPs), although highly effective, are costly and may lead to ectopic bone formation. Platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) offer autologous and regenerative alternatives, although their outcomes remain inconsistent. Electrical stimulation methods, including direct current stimulation (DCS), pulsed electromagnetic fields (PEMF), and capacitive coupling (CC), provide promising adjunctive therapies with varying degrees of invasiveness and clinical support. Low-intensity pulsed ultrasound (LIPUS), although noninvasive and successful in long bone healing, requires further validation for spinal applications. This comparative summary facilitates the evaluation of each modality’s clinical utility, guiding evidence-based decision-making in spinal fusion therapy.

Bone Growth Stimulator	Advantages	Disadvantages
BMPs	Highly effective, Food and Drug Administration approved, reduces reoperation rates.	High cost, potential ectopic bone growth, inflammatory responses.
PRP	Autologous, reduces inflammation, lower cost than BMPs.	Inconsistent efficacy, potential infection risk.
MSCs	Reduces donor site morbidity, potential for autograft replacement.	High variability in cell preparation, limited clinical data.
DCS	Proven efficacy, direct osteogenic stimulation, high fusion rates.	Invasive, risk of infection, cost considerations.
PEMF	Non-invasive, promotes angiogenesis and osteogenesis.	Inconsistent outcomes, cost of equipment, long treatment duration.
CC	Non-invasive, promotes osteoblast differentiation.	Potential skin irritation, requires patient adherence.
LIPUS	Non-invasive, promotes bone healing, high success in long bone fractures.	Limited clinical data in spinal fusion, cost of equipment.

Spinal Fusion (Clinical Applications and Implications)

Although LIPUS has many clinical applications in the fusion of other types of bones, the same cannot be said of spinal fusion. Most spinal-fusion studies using LIPUs are preclinical, with promising results. Zhang et al.⁷¹⁾ and Xu et al.⁷²⁾ discovered success rates for spinal fusion when testing LIPUS on rats. After successful preclinical studies, more clinical research should be conducted to provide sufficient evidence for the use of LIPUS for spinal fusion in humans.

PRP is an alternative bone growth stimulator that researchers are investigating. There have been very few studies on its success rate in spinal fusion, and researchers are still working to determine whether PRP is a safer alternative to BMPs. According to the results of the Kubota et al.¹³⁾ study, 94% of the 50 patients who were treated with PRP had lumbar fusion, compared with 74% who were not treated with PRP. Noguchi et al.³⁶⁾ conducted a study in patients with degenerative kyphoscoliosis, lumbar spinal stenosis, and lumbar spondylolisthesis. Bone fusion was observed in 43% of patients treated with PRP and in 26.1% of those not treated with PRP. Although this shows success in fusion rates, PRP has limitations in contact cases³⁶⁾. Noguchi et al.³⁶⁾ found that bone fusion rates were higher in good-contact cases but did not improve in poor-contact cases. PRP efficacy depends on contact conditions and is considered less reliable than BMPs³⁶⁾. The review article by Cai et al.³⁷⁾ supports this conclusion by stating that PRP does not increase fusion rates, clinical outcomes, or complication rates when used in spinal-fusion surgery. The authors also stated that on the basis of cost-effectiveness, PRP should not be used for spinal fusion surgery.

Stem cell therapy has been proposed as an alternative for bone stimulators in spinal fusion. MSC-based therapies show lower fusion rates than BMPs and lack strong clinical evidence^48,49). Few clinical trials have been conducted for stem cell therapy owing to insignificant and inconclusive results from preclinical trials.

Electrical bone growth stimulators (EBGS) have proved effective in the clinical treatment of spinal fusion. According to the review article by Khalifeh et al.⁷³⁾, multiple studies found that DCS produced an 85% fusion rate and a 90% fusion rate in CC. PEMF also showed high spinal-fusion rates. Weinstein et al.⁶¹⁾ reported that of the 142 patients examined, 88% had successful lumbar spine fusion. Even patients with risk factors showed fusion success rates greater than 80%⁶¹⁾. Weinstein et al.⁶¹⁾ concluded that PEMF is a beneficial tool for spinal fusion, particularly for patients who may have risk factors and experience lower fusion rates than do patients without risk factors. Patel et al.⁷⁴⁾ also reported positive results with PEMF, with the PEMF group comprising 160 patients showing a 90% spine fusion rate compared with the 53 patients in the non-PEMF group showing a fusion rate of 60.4%. Alternatively, Khalifeh et al.⁷³⁾ identified limitations of EBGS, such as technology, clinical efficacy, indication and evidence-based guidelines, cost-effectiveness, and a low risk-to-benefit ratio.

Although BMPs remain standard, LIPUS and EBGS offer promising, cost-effective alternatives. However, EBGS and LIPUS appear to be promising for the future, with advantages such as high fusion rates and potential cost savings in the future.

Discussion

Bone growth stimulators have emerged as important adjuncts in spinal-fusion surgery, aiming to enhance osteogenesis and reduce pseudarthrosis, particularly in high-risk populations. However, their clinical utility must be evaluated in the context of efficacy, complications, cost, and regulatory considerations.

Biological Stimulators: Promise and Pitfalls

Among biological options, BMPs are the most studied and widely used, indicating high fusion rates in ALIF and other procedures. However, their use is tempered by high cost and risk of complications such as ectopic bone formation, radiculitis, and airway compromise in cervical applications. Widespread off-label use raises ethical and regulatory concerns, especially given the limited safety data for non-FDA-approved indications. In contrast, PRP offers a low-risk, autologous option but has inconsistent clinical outcomes, likely due to variability in preparation methods. Although some studies show PRP-enhanced fusion rates, others reveal no benefit―or even worse outcomes―suggesting that PRP's efficacy is highly dependent on context and protocol standardization.

MSC therapy presents a promising autograft alternative, especially when harvested from the iliac crest or adipose tissue. MSCs exhibit strong osteogenic potential, particularly when paired with osteoinductive scaffolds or BMP-2. However, the lack of large-scale clinical trials, variability in cell sourcing, and uncertainty about long-term safety limit their current utility. Off-label use with BMPs in cervical fusion poses notable risks, including ectopic growth and dysphagia, further emphasizing the need for strict regulatory compliance.

EBGS: Evidence and Limitations

Electrical stimulation modalities―DCS, PEMF, and CC―have shown promise in improving fusion outcomes, especially in revision cases or patients with risk factors for nonunion. DCS is invasive but offers strong osteogenic stimulation through direct activation of BMPs and transcription factors such as Runx2. PEMF, a noninvasive approach, acts through the Wnt/β-catenin pathway to enhance osteogenesis and angiogenesis, whereas CC stimulates VGCCs and promotes BMP expression. Despite positive results in both preclinical and clinical studies, variability in treatment protocols and a lack of standardized guidelines hinder broader adoption. Moreover, the distinction between radiographic fusion and functional recovery is often overlooked in the literature, making it difficult to translate radiologic success into meaningful patient outcomes.

LIPUS: Potential with Caveats

LIPUS offers a noninvasive, mechanotransduction-based approach to stimulate bone healing. Preclinical models show favorable results in spinal fusion, but human studies remain limited. A recent meta-analysis identified 13 studies; four studied rats; eight studied rabbits, and one studied dog. These studies revealed 88% fusion rates in LIPUS-treated animals compared with 36% in controls⁷⁵⁾. Another study in rats showed that LIPUS improves spinal fusion through angiogenesis coupled with increased numbers of osteoblasts⁷²⁾. Although LIPUS has not been studied in human spinal fusion, the preclinical studies offer evidence that LIPUS may improve human outcomes. Current limitations in LIPUS research include a lack of human clinical trials, unresolved mechanism for ways LIPUS improves fusion, and variability in ultrasound parameters across studies. Nonetheless, its low complication rate and accessibility make it an attractive option for future research.

Literature Limitations and Future Research Needs

A major limitation across the reviewed literature is methodological heterogeneity. Variation in outcome measures, follow-up duration, imaging modalities, and adjunctive therapies complicates comparative analysis. Many studies lack power, long-term data, or control for confounders such as smoking status and comorbidities. Moreover, cost-effectiveness data are sparse, despite the high financial burden of spinal-fusion procedures. Industry sponsorship and potential publication bias further cloud the evidence base.

Conclusion

Bone growth stimulators offer significant potential to improve spinal fusion outcomes, but their optimal application remains unclear owing to inconsistent clinical data, variability in protocols, and underexplored safety profiles. Future research should prioritize direct comparisons of stimulators, long-term outcome studies, and standardized methodologies to assess both radiographic fusion and patient-reported benefits. Novel combinations―such as MSCs with LIPUS or PRP with PEMF―also merit exploration to maximize synergy and safety. With better evidence, clinicians can tailor bone growth strategies to patient needs, improving outcomes while reducing complications and costs.

Author Contributions: T.P.M.: Writing - Reviewing and Editing, Writing - Original Draft, Project Administration, Supervision, References, Discussion, and Conclusion. A.E.: Writing - Original Draft. D.F.: Writing - Original Draft, Visualization. J.B.: Writing - Original Draft, Visualization. A.L.: Writing - Original Draft, Visualization. A.V.: Writing - Original Draft, Visualization.

Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.

Data Availability Statement: All data supporting the findings of this review are contained within the article. No additional data are available.

Ethical Approval and Informed Consent: This study did not require institutional review board approval or informed consent because it is a review article and does not involve human participants, identifiable data, or animal subjects.