Bilateral Slipped Capital Femoral Epiphysis in a Young Girl Treated With Chemotherapy: A Case Report.

CASE: A 1-year-old girl was treated with chemotherapy and hematopoietic stem cell transplantation because of CD40 ligand deficiency. Four years later, she presented with pain in her right leg, diagnosed as atypical acute slipped capital femoral epiphysis, without a clear cause, besides chemotherapy possibly. She was treated with fixation of the epiphysis with a cannulated screw. Two years later, the same diagnosis was made for the left hip and the same surgery was applied. After the 2-year follow-up, clinical outcomes were good. CONCLUSION: Chemotherapy may be a risk factor for atypical slipped capital femoral epiphysis, even without the combination with radiotherapy.

Trained innate immunity modulates osteoblast and osteoclast differentiation.

Macrophages are key regulators in bone repair and regeneration. Recent studies have shown that long-term epigenetic changes and metabolic shifts occur during specific immune training of macrophages that affect their functional state, resulting in heightened (trained) or reduced (tolerant) responses upon exposure to a second stimulus. This is known as innate immune memory. Here, we study the impact of macrophages' memory trait on osteoblast differentiation of human mesenchymal stromal cells (hMSCs) and osteoclast differentiation. An in vitro trained immunity protocol of monocyte-derived macrophages was employed using inactivated Candida albicans and Bacillus Calmette-Guérin (BCG) to induce a 'trained' state and Pam3CSK4 (PAM) and Lipopolysaccharides (LPS) to induce a 'tolerance' state. Macrophages were subsequently cocultured with hMSCs undergoing osteogenic differentiation during either resting (unstimulated) or inflammatory conditions (restimulated with LPS). Alkaline phosphatase activity, mineralization, and cytokine levels (TNF, IL-6, oncostatin M and SDF-1α) were measured. In addition, macrophages underwent osteoclast differentiation. Our findings show that trained and tolerized macrophages induced opposing results. Under resting conditions, BCG-trained macrophages enhanced ALP levels (threefold), while under inflammatory conditions this was found in the LPS-tolerized macrophages (fourfold). Coculture of hMSCs with trained macrophages showed mineralization while tolerized macrophages inhibited the process under both resting and inflammatory conditions. While osteoclast differentiation was not affected in trained-macrophages, this ability was significantly loss in tolerized ones. This study further confirms the intricate cross talk between immune cells and bone cells, highlighting the need to consider this interaction in the development of personalized approaches for bone regenerative medicine.

The risk of delayed spinal cord injury in pediatric spinal deformity surgery.

Delayed spinal cord injury (SCI) hours or days after surgery, with uneventful monitoring and initial normal postoperative neurological examination, is a rare complication. Based on anecdotal evidence, the risk of delayed spinal cord injury might be higher than previously assumed. Therefore the aim of this study was to determine the risk of delayed SCI after pediatric spinal deformity surgery between 2013-2019 in the Netherlands. The total number of pediatric spinal deformity surgeries performed for scoliosis or kyphosis between 2013-2019 was obtained from the Dutch National Registration of Hospital Care. All eleven Dutch hospitals that perform pediatric spinal deformity surgery were contacted for occurrence of delayed SCI. From the identified patients with delayed SCI, the following data were collected: patient characteristics, details about the SCI, the surgical procedure, management and degree of improvement.2884 pediatric deformity surgeries were identified between 2013-2019. Seven patients (0.24%) with delayed SCI were reported: 3 idiopathic, 2 neuromuscular (including 1 kypho-scoliosis) and 2 syndromic scoliosis. The risk of delayed SCI after pediatric deformity surgery was 1:595 in idiopathic scoliosis, 1:214 in syndromic scoliosis, 1:201 in neuromuscular scoliosis. All seven patients had a documented normal neurological examination in the first postoperative period; neurological deficits were first diagnosed at a median 16h (range 2.5-40) after surgery. The risk of delayed SCI after pediatric deformity surgery is higher than previously reported, especially in patients with non-idiopathic scoliosis. Regular postoperative testing for late neurologic deficit should be performed for timely diagnosis and management of this devastating complication.

Did the dislocation risk after primary total hip arthroplasty decrease over time? A meta-analysis across six decades.

BACKGROUND: While continuous optimization is attempted to decrease the incidence of dislocation after total hip arthroplasty (THA), dislocation remains a major complication. This meta-analysis aims to analyze the evolution of the dislocation risk after primary THA over the decades and to evaluate its potential publication bias. PATIENTS AND METHODS: A systematic search was performed according to the PRISMA guidelines for this meta-analysis in the literature published between 1962 and 2020. MEDLINE, Cochrane and Embase databases were searched for studies reporting the dislocation risk and length of follow-up. Studies that reported on revision rates only and did not mention separate dislocations were excluded. All study designs were eligible. Study quality was assessed by existing quality assessment tools adjusted for arthroplasty research. Overall risk and yearly dislocation rates were calculated and related to historical time frame, study design, sample size and length of follow-up. RESULTS: In total, 174 studies were included with an overall moderate quality. In total there were 85.209 dislocations reported in 5.030.293 THAs, showing an overall dislocation risk of 1.7%, with a median follow-up of 24 months. The overall dislocation risk classified per decade decreased from 3.7% in 1960-1970 to 0.7% in 2010-2020. The yearly dislocation rate decreased from 1.8 to 0.7% within these same decades. There was no significant correlation between the reported dislocation risk and the duration of follow-up (p = 0.903) or sample size (p = 0.755). The reported dislocation risk was higher in articles with registry data compared to other study designs (p = 0.021). CONCLUSION: The dislocation risk in THA has been decreasing over the past decades to 0.7%. Non-selective registry studies reported a higher dislocation risk compared to studies with selective cohorts and RCTs. This indicates that the actual dislocation risk is higher than often reported and 'real-world data' are reflected better in large-scale cohorts and registries.

CT analysis of the posterior anatomical landmarks of the scoliotic spine.

AIM: To use computed tomography (CT) to assess the validity and reliability of the posterior landmarks, spinous processes (SP), transverse processes (TP), and centre of lamina (COL), as compared to the Cobb angle to assess the curve severity and progression of adolescent idiopathic scoliosis (AIS). MATERIALS AND METHODS: A consecutive series of CT examinations of severe AIS patients were included retrospectively. SP, TP, and COL angles were measured for all curves and compared to the Cobb angle. RESULTS: One hundred and five patients were included. The mean Cobb versus SP, TP, and COL angles were, 54° versus 37°, 49°, and 51° in the thoracic curves and 34° versus 26°, 31°, and 34° in the (thoraco)lumbar curves. Intraclass correlation coefficient values for intra-rater measurements of the SP, TP, and COL angles were 0.93, 0.97, and 0.95 and 0.70, 0.90, and 0.88 for inter-rater measurements. The correlations between the Cobb angle and SP, TP, and COL angles in thoracic and (thoraco)lumbar curves were 0.79 and 0.66, 0.87 and 0.84, and 0.80 and 0.70. CONCLUSIONS: The posterior spinal landmarks can be used for assessment of scoliosis severity in AIS; however, they show a systematic underestimation, but a strong correlation with the coronal Cobb angle. TP and COL angles had the highest validity.

The atonic stomach: a dangerous condition prior to scoliosis surgery.

A dilated atonic stomach as part of neuromuscular or syndromic disorders can have devastating results after scoliosis surgery. Patients can be asymptomatic preoperatively and non-clinical signs can be easily overlooked. Awareness of the condition, however, can prevent severe complications such as aspiration.

Variations in the sagittal plane precede the development of scoliosis: a proof of concept.

Idiopathic scoliosis in man is believed to be related to the unique human sagittal profile. Patients with a thoracic scoliosis have a longer, more proximal, posteriorly inclined segment of the spine as compared to lumbar scoliosis and controls, whereas patients with a lumbar scoliosis have a more caudal, shorter and steeper posteriorly inclined segment. In 22q11.2 deletion syndrome, half of the patients develop a scoliosis that is very similar to idiopathic scoliosis and may serve as a model for the general population. In our center, all patients with 22q11.2 deletion syndrome older than 6 years receive standardized radiographic spine imaging every 2 years to screen for scoliosis. In this prospective proof-of-principle study the goal was to determine whether there are differences in sagittal alignment between patients that develop scoliosis vs. controls before the onset of scoliosis, and obtain data to perform a power calculation for future studies. To capture the sagittal shape of the spine into one risk factor for development for scoliosis, we combined relative length and magnitude of dorsal inclination into a new parameter: the posterior inclined triangle surface (PITS). We included 31 patients with initially straight spines, five developed a thoracic scoliosis and seven developed a (thoraco)lumbar scoliosis after a mean follow-up of 3.4 years. The PITS was considerably higher in the group that developed scoliosis as compared to the controls (59 vs 43). Based on this pilot study, we have identified a potential overall sagittal profile risk parameter for the development of idiopathic scoliosis.

Anterior lengthening in scoliosis occurs only in the disc and is similar in different types of scoliosis.

Relative anterior spinal overgrowth (RASO) was proposed as a generalized growth disturbance and a potential initiator of adolescent idiopathic scoliosis (AIS). However, anterior lengthening was also observed in neuromuscular (NM) scoliosis, was shown to be restricted to the apical areas and to be located in the intervertebral discs, not in the bone. In this study the goal was to determine if other scoliotic curves of known origin exhibit the similar mechanism of anterior lengthening without changes in the vertebral body. Therefore CT-scans of 18 patients in whom a short segment congenital malformation had led to a long thoracic compensatory curve without bony abnormality were included. Of each vertebral body and intervertebral disc in the compensatory curve, the anterior and posterior length was measured on CT-scans in the exact mid-sagittal plane, corrected for deformity in all three planes. The total AP% of the compensatory curve in congenital scoliosis showed a lordosis (+1.8%) that differed from the kyphosis in non-scoliotic controls (-3.0%; p<0.001), and was comparable to AIS (+1.2%) and NM scoliosis (+0.5%). This anterior lengthening was not located in the bone; the vertebral body AP% showed a kyphosis (-3.2%), similar to non-scoliotic controls (-3.4%), as well as AIS (-2.5%) and NM scoliosis (-4.5%; p=1.000). However, the disc AP% showed a lordosis (+24.3%), which sharply contrasts to the kyphotic discs of controls (-1.5%; p<0.001), but was similar to AIS (+17.5%) and NM scoliosis (+20.5%). The results demonstrate that anterior lengthening is part of the three-dimensional deformity in different types of scoliosis and is exclusively located in the intervertebral discs. The bony vertebral bodies maintain their kyphotic shape, which indicates that there is no active bony overgrowth. Anterior lengthening appears to be a passive result of any scoliotic deformity, rather than being related to the specific cause of AIS.

Spring distraction system to correct early onset scoliosis: 2 year follow-up results from 24 patients.

Current surgical treatment options for Early Onset Scoliosis (EOS), with distraction- or growth-guidance systems, show limited growth and high complication rates. We developed the Spring Distraction System (SDS), which does not have to be periodically lengthened and which provides continuous corrective force to stimulate spinal growth. This study aimed to assess curve correction and maintenance, spinal growth, and complication rate following SDS treatment. All primary- and revision patients (conversion from failed other systems) with SDS and ≥2 years follow-up were included. Outcome measures were coronal Cobb angle, sagittal parameters, spinal length measurements and complications and re-operations. Radiographic parameters were compared pre-operatively, post-operatively and at latest follow-up. Spinal length increase was expressed as mm/year. Twenty-four skeletally immature EOS patients (18 primary and 6 revision cases) were included. There were 5 idiopathic, 7 congenital, 3 syndromic and 9 neuromuscular EOS patients. Mean age at implantation was 9.1 years (primary: 8.4; conversion: 11.2). Major curve improved from 60.3° to 35.3°, and was maintained at 40.6° at latest follow-up. Mean spring length increase during follow-up was 10.4mm/year. T1-S1 length increased 13.6mm/year and the instrumented segment length showed a mean increase of 0.8mm/segment/year. In total, 17 re-operations were performed. Ten re-operations were performed to treat 9 implant-related complications. In addition, 7 patients showed spinal growth that exceeded expected growth velocity; their springs were re-tensioned during a small re-operation. Spring distraction may be feasible as an alternative to current growing spine solutions. Curve correction and growth could be maintained satisfactory without the need for repetitive lengthening procedures. Complications and re-operations could not be prevented, which emphasizes the need for further improvement.

Halo pin positioning in the temporal bone; parameters for safe halo gravity traction.

INTRODUCTION: Halo gravity traction (HGT) is increasingly used pre-operatively in the treatment of children with complex spinal deformities. However, the design of the current halo crowns is not optimal for that purpose. To prevent pin loosening and to avoid visual scars, fixation to the temporal area would be preferable. This study aims to determine whether this area could be safe for positioning HGT pins. METHODS: A custom made traction setup plus three human cadaver skulls were used to determine the most optimal pin location, the resistance to migration and the load to failure on the temporal bone. A custom-made spring-loaded pin with an adjustable axial force was used. For the migration experiment, this pin was positioned at 10 predefined anatomical areas in the temporal region of adult cadaver skulls, with different predefined axial forces. Subsequently traction force was applied and increased until migration occurred. For the load-to-failure experiment, the pin was positioned on the most applicable temporal location on both sides of the skull. RESULTS: The most optimal position was identified as just antero-cranial to the auricle. The resistance to migration was clearly related to the axial tightening force. With an axial force of only 100 N, which corresponds to a torque of 0.06 Nm (0.5 in-lb), a vertical traction force of at least 200 N was needed for pin migration. A tightening force of 200 N (torque 0.2 Nm or 2 in-lb) was sufficient to resist migration at the maximal applied force of 360 N for all but one of the pins. The load-to-failure experiment showed a failure range of 780-1270 N axial force, which was not obviously related to skull thickness. CONCLUSION: The temporal bone area of adult skulls allows axial tightening forces that are well above those needed for HGT in children. The generally applied torque of 0.5 Nm (4 in-lb) which corresponds to about 350 N axial force, appeared well below the failure load of these skulls and much higher than needed for firm fixation.

Long-term (> 10 years) clinical outcomes of instrumented posterolateral fusion for spondylolisthesis.

PURPOSE: Despite the rapid increase in instrumented spinal fusions for a variety of indications, most studies focus on short-term fusion rates. Long-term clinical outcomes are still scarce and inconclusive. This study investigated clinical outcomes > 10 years after single-level instrumented posterolateral spinal fusion for lumbar degenerative or isthmic spondylolisthesis with neurological symptoms. METHODS: Cross-sectional long-term follow-up among the Dutch participants of an international multicenter randomized controlled trial comparing osteogenic protein-1 with autograft. Clinical outcomes were assessed using the Oswestry Disability Index (ODI), EQ-5D-3L and visual analogue scale (VAS) for leg and back pain, as well as questions on satisfaction with treatment and additional surgery. RESULTS: The follow-up rate was 73% (41 patients). At mean 11.8 (range 10.1-13.7) years after surgery, a non-significant deterioration of clinical outcomes compared to 1-year follow-up was observed. The mean ODI was 20 ± 19, mean EQ-5D-3L index score 0.784 ± 0.251 and mean VAS for leg and back pain, respectively, 34 ± 33 and 31 ± 28. Multiple regression showed that diagnosis (degenerative vs. isthmic spondylolisthesis), graft type (OP-1 vs. autograft) and 1-year fusion status (fusion vs. no fusion) were not predictive for the ODI at long-term follow-up (p = 0.389). Satisfaction with treatment was excellent and over 70% of the patients reported lasting improvement in back and/or leg pain. No revision surgeries for non-union were reported. CONCLUSION: This study showed favourable clinical outcomes > 10 years after instrumented posterolateral spinal fusion and supports spondylolisthesis with neurological symptoms as indication for fusion surgery.

Surgical Restoration of Sagittal Alignment of the Spine: Correlation with Improved Patient-Reported Outcomes: A Systematic Review and Meta-Analysis.

BACKGROUND: The sagittal-plane curvatures of the human spine are the consequence of evolution from quadrupedalism to bipedalism and are needed to maintain the center of mass of the body within the base of support in the bipedal position. Lumbar degenerative disorders can lead to a decrease in lumbar lordosis and thereby affect overall alignment of the spine. However, there is not yet enough direct evidence that surgical restoration of spinal malalignment would lead to a better clinical outcome. Therefore, the aim of this study was to assess the correlation between patient-reported outcomes and actual obtained spinal sagittal alignment in adult patients with lumbar degenerative disorders who underwent surgical treatment. METHODS: A comprehensive literature search was conducted through databases (PubMed, Cochrane, Web of Science, and Embase). The last search was in November 2018. Risk of bias was assessed with the Newcastle-Ottawa quality assessment scale. A meta-regression analysis was performed. RESULTS: Of 2,024 unique articles in the original search, 34 articles with 973 patients were included. All studies were either retrospective or prospective cohort studies; no randomized controlled trials were available. A total of 54 relations between preoperative-to-postoperative improvement in patient-reported outcome measures (PROMs) and radiographic spinopelvic parameters were found, of which 20 were eligible for meta-regression analysis. Of these, 2 correlations were significant: pelvic tilt (PT) versus Oswestry Disability Index (ODI) (p = 0.009) and PT versus visual analog scale (VAS) pain (p = 0.008). CONCLUSIONS: On the basis of the current literature, lower PT was significantly correlated with improved ODI and VAS pain in patients with sagittal malalignment caused by lumbar degenerative disorders that were treated with surgical correction of the sagittal balance. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The role of bacterial stimuli in inflammation-driven bone formation.

Immune cells and their soluble factors regulate skeletal cells during normal bone regeneration and pathological bone formation. Bacterial infections can trigger immune responses that activate pro-osteogenic pathways, but these are usually overshadowed by osteolysis and concerns of systemic inflammation. The aim of this study was to determine whether the transient local inflammatory reaction to non-viable bacterial immune agonists could lead to favourable new bone formation. In a series of rabbit studies, as proof-of-concept, how tibial intramedullary injection of viable or killed bacterial species affected bone remodelling and new bone formation was determined. Application of killed bacteria led to considerable new bone formation after 4 weeks, without the prolonged systemic inflammation and exaggerated bone lysis seen with active infection. The osteo-immunomodulatory effects of various species of killed bacteria and the dose response relationship were subsequently screened in ectopically-implanted ceramic scaffolds. Histomorphometry after 8 weeks showed that a relatively low dose of killed bacteria enhanced ectopic bone induction. Moreover, lipoteichoic acid - the bacterial cell-wall derived toll-like-receptor (TLR)-2 activator - was identified as an osteo-stimulatory factor. Collectively, the data indicated that bacterial stimuli could be harnessed to stimulate osteogenesis, which occurs through a synergy with osteoinductive signals. This finding holds promise for the use of non-viable bacteria, bacterial antigens, or their simplified analogues as immuno-modulatory bone regenerating tools in bone biomaterials.

Celiac Artery Syndrome After Correction of Kyphoscoliosis.

Compression of the celiac artery by a tight arcuate ligament of the diaphragm is a rare syndrome that can arise after correction of severe kyphosis. Symptoms include abdominal pain and ileus and liver dysfunctions. These symptoms can be easily attributed to more common causes like the superior mesenteric artery syndrome, and a delay in the diagnosis of celiac artery obstruction may result in severe ischemic disease of the gastrointestinal tract. We present a case of celiac artery syndrome after correction of a kyphoscoliosis with severe sequelae that has not been documented before.

Neurological Outcome After Traumatic Transverse Sacral Fractures: A Systematic Review of 521 Patients Reported in the Literature.

BACKGROUND: The purpose of this study was to determine the neurological outcome after transverse sacral fractures in patients with neurological impairment. METHODS: A systematic review of the English, French, German, and Dutch literature was conducted. All study designs, including retrospective cohort studies and case reports, describing transverse sacral fractures were included. Two authors independently extracted the predefined data and scored the neurological impairment according to the Gibbons classification after the trauma and at the time of follow-up. The neurological outcomes were pooled according to the Gibbons classification. RESULTS: No randomized controlled trials or prospective case series were found. A total of 139 articles were included, consisting of 81 case reports and 58 retrospective case series involving 521 patients. Regardless of the type of management, neurological recovery of at least 1 Gibbons category was reported in 62% of these patients. A comparison of the neurological outcome of nonoperatively treated patients and surgically treated patients showed similar neurological recovery rates. For the surgically treated patients, fixation of the fracture resulted in a better neurological improvement compared with an isolated decompression. CONCLUSIONS: This review could not provide evidence of improved neurological recovery after surgical treatment compared with nonoperative treatment. When surgical treatment was considered, there was a low level of evidence that fixation of the fracture results in better neurological improvement compared with isolated decompression. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Interleukin 17 enhances bone morphogenetic protein-2-induced ectopic bone formation.

Interleukin 17 (IL-17) stimulates the osteogenic differentiation of progenitor cells in vitro through a synergy with bone morphogenetic protein (BMP)-2. This study investigates whether the diverse responses mediated by IL-17 in vivo also lead to enhanced BMP-2-induced bone formation. Since IL-17 is known to induce osteoclastogenesis, we studied the interactions between IL-17 and BMP-2 in ceramic scaffolds either or not carrying a coating with the bisphosphonate zoledronic acid (ZOL). Histological evaluation revealed that IL-17 alone did not induce any osteoclasts at day 10. On the other hand, BMP-2 clearly stimulated early tissue ingrowth and osteoclastogenesis. Both of these processes were blocked in presence of ZOL. IL-17 signaling restored early vascularized connective tissue formation and osteoclastogenesis induced by BMP-2 in ZOL-coated scaffolds. After 12 weeks, the bone volume induced by co-delivery of BMP-2 and IL-17 was doubled as compared to that induced by BMP-2 alone. We conclude that IL-17 has osteo-stimulatory effects through a synergy with bone-inductive BMP-2. Although local and single application of IL-17 does not mediate osteoclast formation, it could promote other processes involved in bone formation such as connective tissue ingrowth. The use of IL-17 may contribute to the development of improved bone graft substitutes.

Bone formation by heterodimers through non-viral gene delivery of BMP-2/6 and BMP-2/7.

Non-viral gene delivery is a safe technique to release sustained physiologic dosages of bone morphogenetic protein (BMP). Co-delivery of multiple BMPs can result in the formation of more potent BMP heterodimers. In this study, non-viral co-delivery of BMP-2/6 and BMP-2/7, as a mean to produce heterodimers, was assessed. Goat MSCs were non-virally transfected with plasmid DNA encoding BMP isoforms (pBMP) known to be relevant for osteogenesis: BMP-2, -6 or -7. As a result, BMP-2, -6 and -7 were produced and detectable for up to 14 d and their combined delivery (pBMP-2 with pBMP-6 or pBMP-7) was used to create BMP-2/6 and BM-2/7 heterodimers. Formation and secretion of the heterodimer proteins was validated by sandwich enzyme-linked immunosorbent assay (ELISA). Produced BMPs and heterodimers were biologically active, as confirmed by differentiation of reporter cells and MSCs. To assess bone formation, transfected MSCs were seeded on to ceramic scaffolds and implanted subcutaneously into nude mice. Bone formation was significantly enhanced in the pBMP-2/6 condition and a trend for more bone formation was observed in the pBMP-2/7 and pBMP-6 homodimer condition. No bone was found in the pBMP-2, pBMP-7 or control condition. In conclusion, simultaneous delivery of pBMP-2 with pBMP-6 or -7 resulted in the production of heterodimers that were beneficial for bone formation as compared to BMP homodimers. Combination of BMP sequences could reduce the need for high BMP protein dosages and might enhance prolonged availability of the growth factors.

Local induction of inflammation affects bone formation.

To explore the influence of inflammatory processes on bone formation, we applied a new in vivo screening model. Confined biological pockets were first created in rabbits as a response to implanted bone cement discs. These biomembrane pockets were subsequently used to study the effects of inflammatory stimuli on ectopic bone formation within biphasic calcium phosphate (BCP) constructs loaded with TNF-α, lipopolysaccharide (LPS) or lipoteichoic acid (LTA), all with or without bone morphogenetic protein (BMP)-2. Analysis of bone formation after 12 weeks demonstrated that the inflammatory mediators were not bone-inductive in combination with the BCP alone, but inhibited or enhanced BMP-induced bone formation. LPS was associated with a strong inhibition of bone formation by BMP-2, while LTA and TNF-α showed a positive interaction with BMP-2. Since the biomembrane pockets did not interfere with bone formation and prevented the leakage of pro-inflammatory compounds to the surrounding tissue, the biomembrane model can be used for in vivo approaches to study local inflammation in conjunction with new bone formation. Using this model, it was shown that the modulation of the inflammatory response could be beneficial or detrimental to the subsequent bone formation process. The co-delivery of inflammatory factors and bone-related growth factors should be further explored as a strategy to enhance the bone-forming efficacy of bone substitutes.