Small extracellular vesicles from mesenchymal stromal cells: the next therapeutic paradigm for musculoskeletal disorders.

Musculoskeletal disorders are one of the biggest contributors to morbidity and place an enormous burden on the health care system in an aging population. Owing to their immunomodulatory and regenerative properties, mesenchymal stromal/stem cells (MSCs) have demonstrated therapeutic efficacy for treatment of a wide variety of conditions, including musculoskeletal disorders. Although MSCs were originally thought to differentiate and replace injured/diseased tissues, it is now accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly extracellular vesicles (EVs). Endowed with a diverse cargo of bioactive lipids, proteins, nucleic acids and metabolites, MSC-EVs have been shown to elicit diverse cellular responses and interact with many cell types needed in tissue repair. The present review aims to summarize the latest advances in the use of native MSC-EVs for musculoskeletal regeneration, examine the cargo molecules and mechanisms underlying their therapeutic effects, and discuss the progress and challenges in their translation to the clinic.

Orthopedic concerns of a child with short stature.

PURPOSE OF REVIEW: Pediatric short stature poses severe concerns to the patient, parents, and physicians. Management for pediatric short stature is still widely debated due to heterogenous etiological factors and treatment options. This review will address the approach to pediatric short stature, commonly within the subset of skeletal dysplasia resulting in disproportionate short stature. The following will be discussed: the etiology, clinical, and radiological evaluations, and management for pediatric short stature. RECENT FINDINGS: Early recognition of short stature and appropriate referrals is shown to benefit the patient and reduce parental concern. A multidisciplinary team, comprising an orthopedic surgeon, is fundamental to provide holistic care and ensure overall good quality of life. Advancements in clinical diagnostic tools and diversified treatment modalities today provides optimism in managing pediatric short stature. SUMMARY: Skeletal dysplasia can be treated with good prognosis if diagnosed and managed early. Thorough clinical, radiological, laboratory, and even genetic investigations are important to differentiate and manage various types of skeletal dysplasia. Our review will provide a comprehensive and up-to-date approach to skeletal dysplasia for pediatric orthopedic surgeons, and indications for physicians to refer patients with suspected short stature to pediatric orthopedic surgeons.

Intra-Articular Injections of Mesenchymal Stem Cell Exosomes and Hyaluronic Acid Improve Structural and Mechanical Properties of Repaired Cartilage in a Rabbit Model.

PURPOSE: To compare the efficacy of mesenchymal stem cell (MSC) exosomes with hyaluronic acid (HA) against HA alone for functional cartilage regeneration in a rabbit osteochondral defect model. METHODS: Critical-size osteochondral defects (4.5-mm diameter and 1.5-mm depth) were created on the trochlear grooves in the knees of 18 rabbits and were randomly allocated to 2 treatment groups: (1) exosomes and HA combination and (2) HA alone. Three 1-mL injections of either exosomes and HA or HA alone were administered intra-articularly immediately after surgery and thereafter at 7 and 14 days after surgery. At 6 and 12 weeks, gross evaluation, histologic and immunohistochemical analysis, and scoring were performed. The functional biomechanical competence of the repaired cartilage also was evaluated. RESULTS: Compared with defects treated with HA, defects treated with exosomes and HA showed significant improvements in macroscopic scores (P = .032; P = .001) and histologic scores (P = .005; P < .001) at 6 and 12 weeks, respectively. Defects treated with exosomes and HA also demonstrated improvements in mechanical properties compared with HA-treated defects, with significantly greater Young's moduli (P < .05) and stiffness (P < .05) at 6 and 12 weeks. By 12 weeks, the newly-repaired tissues in defects treated with exosomes and HA composed mainly of hyaline cartilage that are mechanically and structurally superior to that of HA-treated defects and demonstrated mechanical properties that approximated that of adjacent native cartilage (P > .05). In contrast, HA-treated defects showed some repair at 6 weeks, but this was not sustained, as evidenced by significant deterioration of histologic scores (P = .002) and a plateau in mechanical properties from 6 to 12 weeks. CONCLUSIONS: This study shows that the combination of MSC exosomes and HA administered at a clinically acceptable frequency of 3 intra-articular injections can promote sustained and functional cartilage repair in a rabbit post-traumatic cartilage defect model, when compared with HA alone. CLINICAL RELEVANCE: Human MSC exosomes and HA administered in combination promote functional cartilage repair and may represent a promising cell-free therapy for cartilage repair in patients.

MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment.

Mesenchymal stem cell (MSC) therapies have demonstrated efficacy in cartilage repair in animal and clinical studies. The efficacy of MSC-based therapies which was previously predicated on the chondrogenic potential of MSC is increasingly attributed to the paracrine secretion, particularly exosomes. Exosomes are thought to function primarily as intercellular communication vehicles to transfer bioactive lipids, nucleic acids (mRNAs and microRNAs) and proteins between cells to elicit biological responses in recipient cells. For MSC exosomes, many of these biological responses translated to a therapeutic outcome in injured or diseased cells. Here, we review the current understanding of MSC exosomes, discuss the possible mechanisms of action in cartilage repair within the context of the widely reported immunomodulatory and regenerative potency of MSC exosomes, and provide new perspectives for development of an off-the-shelf and cell-free MSC therapy for treatment of cartilage injuries and osteoarthritis.

Cellular senescence in aging and osteoarthritis.

- It is well accepted that age is an important contributing factor to poor cartilage repair following injury, and to the development of osteoarthritis. Cellular senescence, the loss of the ability of cells to divide, has been noted as the major factor contributing to age-related changes in cartilage homeostasis, function, and response to injury. The underlying mechanisms of cellular senescence, while not fully understood, have been associated with telomere erosion, DNA damage, oxidative stress, and inflammation. In this review, we discuss the causes and consequences of cellular senescence, and the associated biological challenges in cartilage repair. In addition, we present novel strategies for modulation of cellular senescence that may help to improve cartilage regeneration in an aging population.

A novel practical method to predict anterior cruciate ligament hamstring graft size using preoperative MRI.

BACKGROUND: Predicting hamstring graft size preoperatively for anterior cruciate ligament (ACL) reconstruction is important for preempting an insufficient diameter in graft size intraoperatively, possibly leading to graft failure. While there are multiple published methods using magnetic resonance imaging (MRI) picture archiving and communication systems (PACS), most are not feasible and practical. Our study aims to (1) practically predict the ACL hamstring graft size in a numerically continuous manner using the preoperative MRI from any native MRI PACS system, (2) determine the degree of correlation between the predicted and actual graft size, and (3) determine the performance of our prediction method if we define an adequate actual graft size as ≥ 8 mm. METHODS: A retrospective review of 112 patients who underwent primary ACL reconstruction with quadrupled hamstring semitendinosus-gracilis grafts at a tertiary institution was conducted between January 2018 and December 2018. Graft diameter can be predicted in a numerically continuous manner as √[2*(AB + CD)], where A and B are the semitendinosus cross-sectional length and breath, respectively, and C and D are the gracilis cross-sectional length and breath, respectively. RESULTS: A moderately positive correlation exists between the predicted and actual graft diameter (r = 0.661 and p < .001). Our method yields a high specificity of 92.6% and a moderate sensitivity of 67.2% if we define an adequate actual graft size as ≥ 8 mm. An area under receiver-operating characteristic curve shows good discrimination (AUC = 0.856). CONCLUSIONS: We present a practical method to predict the ACL hamstring graft size with high specificity using preoperative MRI measurements.

Trochleoplasty Provides Good Outcomes for Recurrent Patellofemoral Dislocations with No Clear Superiority across Different Techniques.

Background: Literature is sparse on outcome comparisons between different trochleoplasty techniques in the treatment of patella instability. To date, it is unclear whether there is a technique that offers superior outcomes. This systematic review and meta-analysis aims to compare and evaluate the outcomes of trochleoplasty techniques in the treatment of patellofemoral instability in trochlea dysplasia to establish whether there is an ideal choice of trochleoplasty technique for superior outcomes. Methods: 21 studies involving 880 knees were included. The mean age of the patients was 21.7 years (range 8-49 years). Mean follow-up timeframe of 43.5 months (range 8.8-100 months). Clinical outcomes assessed included rates of recurrence of patellofemoral dislocation, patient satisfaction, Kujala score, International Knee Documentation Committee (IKDC) score, Tegner score, and Lysholm score. Egger's test showed no publication bias across all outcomes assessed. Results: Favourable results were seen across all outcomes assessed and patient satisfaction. Improvements were seen with Kujala, IKDC, and Lysholm scores. Tegner scores showed good return to function. Post-operative dislocation and complication rates were low across the different techniques. Meta-regression for Kujala and IKDC scores showed good outcomes regardless of trochleoplasty technique used (Kujala, p = 0.549, relative risk 492.06; IKDC, p = 0.193, RR 0.001). The exact risk that trochleoplasty poses to the cartilage remains uncertain, as no study had a conservatively managed arm for comparison. Conclusions: Trochleoplasty yielded good outcomes irrespective of technique used with no clear superiority demonstrated in any technique in terms of outcome scores, satisfaction, post-operative dislocation rates or complications.

Evidence-based status of microfracture technique: a systematic review of level I and II studies.

PURPOSE: Although many newer cartilage repair techniques have evolved over the past 2 decades, microfracture is still being advocated as the first line of treatment. Therefore it is timely to conduct a comprehensive review of the literature to assess and report on the current status of Level I and II evidence studies related to microfracture techniques. METHODS: A literature search was carried out for Level I and II evidence studies on cartilage repair using the PubMed database. All the studies that dealt with microfracture techniques were selected. RESULTS: Fifteen studies that involved microfracture techniques met the inclusion criteria of this review article, with 6 long-term and 9 short-term studies. These studies compared the clinical outcomes of microfracture with those of other treatments such as autologous chondrocyte implantation and osteochondral cylinder transfers. The majority of the studies reported poor clinical outcomes, whereas 2 studies reported the absence of any significant difference in the results. Small-sized lesions and younger patients showed good results in the short-term. However, osteoarthritis and treatment failures were observed at later postoperative periods of 5 to 10 years. CONCLUSIONS: The use of microfracture for the treatment of small lesions in patients with low postoperative demands was observed to result in good clinical outcomes at short-term follow-up. Beyond 5 years postoperatively, treatment failure after microfracture could be expected regardless of lesion size. Younger patients showed better clinical outcomes. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies.

Perspective in Achieving Stratified Articular Cartilage Repair Using Zonal Chondrocytes.

Articular cartilage is composed of superficial, medial, and deep zones, which endow the tissue with biphasic mechanical properties to withstand shearing force and compressional loading. The tissue has very limited self-healing capacity once it is damaged due to its avascular nature. To prevent the early onset of osteoarthritis, surgical intervention is often needed to repair the injured cartilage. Current noncell-based and cell-based treatments focus on the regeneration of homogeneous cartilage to achieve bulk compressional properties without recapitulating the zonal matrix and mechanical properties, and often oversight in aiding cartilage integration between host and repair cartilage. It is hypothesized that achieving zonal architecture in articular cartilage tissue repair could improve the structural and mechanical integrity and thus the life span of the regenerated tissue. Engineering stratified cartilage constructs using zonal chondrocytes have been hypothesized to improve the functionality and life span of the regenerated tissues. However, stratified articular cartilage repair has yet to be realized to date due to the lack of an efficient zonal chondrocyte isolation method and an expansion platform that would allow both cell propagation and phenotype maintenance. Various attempts and challenges in achieving stratified articular cartilage repair in a clinical setting are evaluated. In this review, different perspectives on achieving stratified articular cartilage repair using zonal chondrocytes are described. The effectiveness of different zonal chondrocyte isolation and zonal chondrocyte phenotype maintenance methodologies during expansion are compared, with the focus on recent advancements in zonal chondrocyte isolation and expansion that could present a possible strategy to overcome the limitation of applying zonal chondrocytes to facilitate zonal architecture development in articular cartilage regeneration. Impact Statement The zonal properties of articular cartilage contribute to the biphasic mechanical properties of the tissues. Recapitulation of the zonal architecture in regenerated articular cartilage has been hypothesized to improve the mechanical integrity and life span of the regenerated tissue. This review provides a comprehensive discussion on the current state of research relevant to achieving stratified articular cartilage repair using zonal chondrocytes from different perspectives. This review further elaborates on a zonal chondrocyte production pipeline that can potentially overcome the current clinical challenges and future work needed to realize stratified zonal chondrocyte implantation in a clinical setting.

Managing the Heterogeneity of Mesenchymal Stem Cells for Cartilage Regenerative Therapy: A Review.

Articular cartilage defects commonly result from trauma and are associated with significant morbidity. Since cartilage is an avascular, aneural, and alymphatic tissue with a poor intrinsic healing ability, the regeneration of functional hyaline cartilage remains a difficult clinical problem. Mesenchymal stem cells (MSCs) are multipotent cells with multilineage differentiation potential, including the ability to differentiate into chondrocytes. Due to their availability and ease of ex vivo expansion, clinicians are increasingly applying MSCs in the treatment of cartilage lesions. However, despite encouraging pre-clinical and clinical data, inconsistencies in MSC proliferative and chondrogenic potential depending on donor, tissue source, cell subset, culture conditions, and handling techniques remain a key barrier to widespread clinical application of MSC therapy in cartilage regeneration. In this review, we highlight the strategies to manage the heterogeneity of MSCs ex vivo for more effective cartilage repair, including reducing the MSC culture expansion period, and selecting MSCs with higher chondrogenic potential through specific genetic markers, surface markers, and biophysical attributes. The accomplishment of a less heterogeneous population of culture-expanded MSCs may improve the scalability, reproducibility, and standardisation of MSC therapy for clinical application in cartilage regeneration.

Risk factors for a false negative Ortolani and Barlow examination in developmental dysplasia of the hip.

INTRODUCTION: Although universal screening by neonatal clinical examination with Ortolani and Barlow manoeuvres is widely adopted, its role as a sole screening tool is controversial due to its poor sensitivity and failure in identifying hip joints that eventually require surgical intervention. HYPOTHESIS: This study aims to identify risk factors for a false negative Ortolani and Barlow examination in neonatal screening for DDH. The hypothesis is that risk factors for developmental dysplasia of the hips could similarly be risk factors for a false negative Ortolani and Barlow examination. MATERIAL AND METHODS: In the 14-year retrospective cohort study, all newborn infants born in a single institution from 1st January 1999 to 31st December 2013 were screened clinically with the Ortolani/Barlow manoeuvre by a neonatologist. Infants with positive risk factors, despite a normal clinical examination, were then scheduled for bilateral hip ultrasound in the first three months of life and evaluated according to the Graf's method, Harcke's method of dynamic ultrasound screening and Terjesen's method of evaluation for femoral head coverage. RESULTS: A total of 164 infants with normal Ortolani and Barlow examinations were scheduled for bilateral hip ultrasound due to the presence of risk factors. Amongst these, 32 (19.5%) infants were evaluated to have an abnormal hip on ultrasound. Breech position was the only statistically significant risk factor for a false negative Ortolani/Barlow examination (14/34, 41.2% vs. 18/112, 13.8%; p<0.001). DISCUSSION: Sonographic hip examinations are recommended for all infants with breech presentation even if they have a normal Ortolani and Barlow examination. LEVEL OF EVIDENCE: III; case-control study.

Do meniscal repairs with meniscus cyst do better than meniscectomy?-a systematic review of meniscal cyst treatment.

Background: This systematic review aims to determine the best modality for the management of meniscal cysts and its associated meniscus tear; whether the meniscal cyst treated via arthroscopy or open methods and whether meniscal debridement or repair achieves better results. Methods: This systematic review was performed using PRISMA guidelines. A literature search of PubMed, EMBASE and Cochrane was carried out in July 2020 using the search terms 'meniscal cyst' and 'treatment'. All clinic studies that included filters for papers in the last 20 years, English language, and meniscal cysts found in humans were included. Studies that contained case reports, were in any language other than English, and with subjects that were not humans were excluded. The methodology quality assessment was performed through the modified Coleman methodology score (CMS). Results: A total of 166 results were obtained from PubMed, Cochrane library and EMBASE. Of them, 12 duplicates were identified across the databases and removed from consideration. Six papers were found relevant from EMBASE in which 1 was eventually included in this paper. In total, 12 papers were used in this study. The weighted mean age of the patients was 35.1 years, with total of 523 meniscal cysts, of which 488 of these cysts are associated with meniscal tears (93.31%). The studies included performed cystectomies and/or decompression of meniscal cysts while some left the meniscal cyst alone and dealt with the meniscal lesion instead. All clinical scores showed significant improvement following surgical procedures. Conclusions: Both arthroscopic and open methods can be used for meniscal cysts treatment. Open cystectomy rather than decompression seemed to confer lower risk of cyst recurrences and complications. It is inconclusive to whether meniscal repair or meniscus debridement influenced recurrence and outcome scores. A recommendation for meniscus repair cannot be made due to insufficient high-quality level I or II trials.

Surgical outcomes in paediatric lateral condyle non-union: A systematic review and meta-analysis.

AIMS: Non-union is a known and much-dreaded complication of paediatric lateral condyle fractures. This systematic review aims to pool together individual studies to find out if the timing of fixation and method of fixation impacts surgical outcomes (postoperative union and elbow ROM) in paediatric lateral condyle non-union. METHODS: A systematic review and individual patient data meta-analysis was conducted according to PRISMA guidelines. All surgical studies with original data on pediatric lateral humeral condyle non-union were included. Patients who did not undergo surgical fixation were excluded. RESULTS: A total of 12 studies with 177 patients were included. In total, 159 patients (89.8%) achieved bony union postoperatively while 18 patients (10.2%) did not. Mixed-effects logistic regression showed that percutaneous fixation (p-value=0.020) was associated with lower rates of postoperative union compared to open fixation, whereas the age at surgery did not have a significant impact (p-value=0.401). For elbow ROM, mixed-effects linear regression showed that increased age at surgery (p-value=0.007) and reduction of the fracture fragment (vs. in situ fixation) (p-value=0.041) were associated with reduced postoperative ROM whereas female sex (p-value=0.009) and corrective osteotomy (p-value=0.045) were associated with increased postoperative ROM. CONCLUSION: While the timing of surgical fixation did not significantly impact postoperative bony union, undergoing fixation at an older age was associated with reduced postoperative elbow ROM. In addition, percutaneous fixation may be associated with poorer postoperative union compared to open fixation while anatomical reduction may be associated with reduced postoperative elbow ROM compared to in situ fixation. LEVEL OF EVIDENCE: IV.

Mesenchymal Stem Cell Exosomes Promote Functional Osteochondral Repair in a Clinically Relevant Porcine Model.

BACKGROUND: Previous studies have reported the efficacy of human mesenchymal stem cell (MSC) exosomes for the repair of osteochondral defects in rats and rabbits. However, the safety and efficacy of MSC exosomes remain to be validated in a clinically relevant large animal model. PURPOSE: To validate the safety and efficacy of human MSC exosomes for osteochondral repair in a clinically relevant micropig model. STUDY DESIGN: Controlled laboratory study. METHODS: Bilateral osteochondral defects (6-mm diameter and 1-mm depth) were surgically created in the medial femoral condyles in knees of 12 micropigs. The pigs then received 2-mL intra-articular injections of MSC exosomes and hyaluronic acid (HA) (Exosome+HA) or HA alone after surgery and thereafter at 8 and 15 days. Osteochondral repair was assessed by magnetic resonance imaging (MRI) at 15 days and at 2 and 4 months after surgery as well as by macroscopic, histological, biomechanical, and micro-computed tomography (micro-CT) analyses at 4 months after surgery. RESULTS: Exosome+HA-treated defects demonstrated significantly better MRI scores than HA-treated defects at 15 days and at 2 and 4 months. Additionally, Exosome+HA-treated defects demonstrated functional cartilage and subchondral bone repair, with significantly better macroscopic and histological scores and biomechanical properties (Young modulus and stiffness) than HA-treated defects at 4 months. Micro-CT further showed significantly higher bone volume and trabecular thickness in the subchondral bone of Exosome+HA-treated defects than that of HA-treated defects. Importantly, no adverse response or major systemic alteration was observed in any of the animals. CONCLUSION: This study shows that the combination of MSC exosomes and HA administered at a clinically acceptable frequency of 3 weekly intra-articular injections can promote functional cartilage and subchondral bone repair, with significantly improved morphological, histological, and biomechanical outcomes in a clinically relevant porcine model. CLINICAL RELEVANCE: Our findings provide a robust scientific rationale to support a phase 1/2 clinical trial to test MSC exosomes in patients with osteochondral lesions.

Mesenchymal Stem Cell Exosomes Promote Growth Plate Repair and Reduce Limb-Length Discrepancy in Young Rats.

BACKGROUND: The objective of this study was to examine the therapeutic effects of human mesenchymal stromal/stem cell (MSC) exosomes in a rat model of growth plate injury. METHODS: A growth plate defect was surgically created on the distal part of the right femur of 40 female Sprague-Dawley rats. A single intra-articular injection of 100 µg of MSC exosomes in 100 µL of phosphate-buffered saline solution (PBS), or an equivalent volume of PBS alone, was administered to the right knee immediately after surgery. At 4 and 8 weeks post-treatment, limb length was measured with micro-CT, and tissue repair was assessed with histological, immunohistochemical, and histomorphometric analyses. RESULTS: A single injection of MSC exosomes significantly increased limb length from 3.29 ± 0.07 cm at 4 weeks to 3.37 ± 0.11 cm at 8 weeks (p = 0.047). However, no improvement in limb length was observed in the PBS control group. The limb-length discrepancy between the involved limb and the contralateral limb in the exosome-treated group was significantly less than the discrepancy in the PBS-treated group at both 4 weeks (2.52% ± 1.30% versus 4.11% ± 0.93%; p = 0.006) and 8 weeks (5.27% ± 2.11% versus 8.06% ± 2.56%; p = 0.016). Consistent with the reduced limb-length discrepancy, the exosome-treated defects displayed significantly more chondrocytes (p < 0.05) and a higher area percentage with deposition of sulphated glycosaminoglycan (p < 0.05) and collagen II (p < 0.05) than PBS-treated defects at 8 weeks. However, bone bridge formation was not inhibited in either group. CONCLUSIONS: A single intra-articular injection of MSC exosomes significantly enhanced physeal repair and reduced limb-length discrepancy but did not inhibit bone-bridge formation. CLINICAL RELEVANCE: This proof-of-concept study demonstrates for the first time the potential use of MSC exosomes as a minimally invasive cell-free therapeutic to promote physeal repair and reduce limb-length discrepancy following growth plate injuries.

Osteochondral tissue engineering: Perspectives for clinical application and preclinical development.

The treatment of osteochondral defects (OCD) remains challenging. Among currently available surgical treatments for OCDs, scaffold-based treatments are promising to regenerate the osteochondral unit. However, there is still no consensus regarding the clinical effectiveness of these scaffold-based therapies for OCDs. Previous reviews have described the gradient physiological characteristics of osteochondral tissue and gradient scaffold design for OCD, tissue engineering strategies, biomaterials, and fabrication technologies. However, the discussion on bridging the gap between the clinical need and preclinical research is still limited, on which we focus in the present review, providing an insight into what is currently lacking in tissue engineering methods that failed to yield satisfactory outcomes, and what is needed to further improve these techniques. Currently available surgical treatments for OCDs are firstly summarized, followed by a comprehensive review on experimental animal studies in recent 5 years on osteochondral tissue engineering. The review will then conclude with what is currently lacking in these animal studies and the recommendations that would help enlighten the community in developing more clinically relevant implants. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This review is attempting to summarize the lessons from clinical and preclinical failures, providing an insight into what is currently lacking in TE methods that failed to yield satisfactory outcomes, and what is needed to further improve these implants.

Pediatric Femoral Shaft Fracture: An Age-Based Treatment Algorithm.

PURPOSE: Fractures of the femoral shaft in children are common. The rates of bone growth and remodeling in children vary according to their ages, which affect their respective management. METHODS: This paper evaluates the incidence and patterns of pediatric femoral shaft fracture and the current concepts of treatments available. RESULTS: The type of fracture-closed or open; stable or unstable-needs to be taken into account. Child abuse should be suspected in fractures sustained by infants. For younger children, non-surgical management is preferred, which include Pavlik harness (< 6 months old) and early spica casting (6 months to 6 years old). Older children (> 6 years old) usually benefit from surgical treatments as outcomes of non-surgical alternatives are worse and are associated with prolonged recovery times. These operative measures for older children that are 6-12 years old include elastic stable intramedullary nailing and submuscular plating. Factors to be considered when devising an appropriate intervention include body mass, location of injury, and nature of fracture. For adolescent and skeletally mature teenagers (> 12 years old), rigid antegrade entry intramedullary fixation is indicated. In the event of open fractures or polytrauma, external fixation should be considered as a temporary treatment method for initial fracture stabilization. CONCLUSION: An age-based and evidence-based algorithm has been proposed to guide surgeons in the process of evaluating an appropriate treatment.