Seven-Year Longitudinal Study: Clinical Evaluation of Knee Osteoarthritic Patients Treated with Mesenchymal Stem Cells.

Background/Objectives: Numerous studies have demonstrated the safety and efficacy of intraarticular stem cell injections for treating osteoarthritic knee joints, reporting symptom reduction and pain relief within a few months of treatment. Here, we report the results of a 7-year follow-up after a single intraarticular injection of 0.5-1 × 107 autologous adipose tissue-derived mesenchymal stem cells in patients with OA (Kellgren-Lawrence grade 2 to 4). Methods: Nine patients were treated, and two patients had bilateral disease. Patients were evaluated clinically and radiologically using X-ray and MRI. A comprehensive statistical analysis was undertaken to evaluate the obtained results. Results: All clinical scores and range of motion significantly improved within the first six months after injection. At the 18-month time point, a significant improvement in cartilage structure was observed on MRI while X-ray showed no changes in subchondral bone of distal femur and proximal tibia. At the 60-month time point, the clinical scores were still improved compared to baseline, except for the range of motion, which decreased almost back to the baseline level. At 84 months, the clinical scores decreased significantly toward the baseline level, but the MRI structural characteristics of cartilage still remained significantly better than those measured at baseline. Conclusions: Adipose tissue-derived stem cell therapy has substantial long-term clinical effects on patients with knee osteoarthritis.

Molecular Biomarkers in Perthes Disease: A Review.

BACKGROUND: Perthes disease is a juvenile form of osteonecrosis of the femoral head that affects children under the age of 15. One hundred years after its discovery, some light has been shed on its etiology and the biological factors relevant to its etiology and disease severity. METHODS: The aim of this study was to summarize the literature findings on the biological factors relevant to the pathogenesis of Perthes disease, their diagnostic and clinical significance, and their therapeutic potential. A special focus on candidate genes as susceptibility factors and factors relevant to clinical severity was made, where studies reporting clinical or preclinical results were considered as the inclusion criteria. PubMed databases were searched by two independent researchers. Sixty-eight articles were included in this review. Results on the factors relevant to vascular involvement and inflammatory molecules indicated as factors that contribute to impaired bone remodeling have been summarized. Moreover, several candidate genes relevant to an active phase of the disease have been suggested as possible biological therapeutic targets. CONCLUSIONS: Delineation of molecular biomarkers that underlie the pathophysiological process of Perthes disease can allow for the provision of earlier and more accurate diagnoses of the disease and more precise follow-ups and treatment in the early phases of the disease.

Intra-articular injection of autologous adipose-derived mesenchymal stem cells in the treatment of knee osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease and is considered to be the fourth leading cause of disability and the second cause of inability to work in men. Recently, adipose-derived mesenchymal stem cells (AD-MSCs) came into focus for regenerative medicine as a promising tool for the treatment of OA. The administration of stem cells into impaired joints results in pain relief and improves quality of life, accompanied by restoration of hyaline articular cartilage. METHODS: In the present study, nine patients (including two patients with bilateral symptoms) diagnosed with osteoarthritis (International Knee Documentation grade B in 5 and grade D in six knees) were treated using a single injection of AD-MSCs at a concentration of 0.5-1.0 × 107 cells and were followed up for 18 months. During follow-up, all the cases were evaluated clinically by Knee Society score (KSS), Hospital for Special Surgery knee score (HSS-KS), Tegner-Lysholm (T-L) score and visual analogue scale (VAS) of pain, as well as by plain radiography and by magnetic resonance imaging visualization with 2D Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score assessment. RESULTS: Significant improvement of all four clinical scores was observed within the first 6 months (KSS for 41.4 points, HSS-KS for 33.9 points, T-L score for 44.8 points, VAS of pain from 54.5 to 9.3) and improvement persisted throughout the rest of the follow-up. MOCART score showed significant cartilage restoration (from 43 ± 7.2 to 63 ± 17.1), whereas radiography showed neither improvement, nor further joint degeneration. CONCLUSIONS: The results obtained in the present study provide good basis for prospective randomized controlled clinical trials with respect to the use of AD-MSCs in the treatment of osteoarthritis.

Predictive genetic markers of coagulation, inflammation and apoptosis in Perthes disease­Serbian experience.

UNLABELLED: Perthes disease is one of the most common forms of pediatric femoral head osteonecrosis with an unknown etiology. Coagulation factors were the first genetic factors suspected to have a role in the pathogenesis of this disease, but studies showed inconsistent results. It is described that inflammation is present during early stages of Perthes disease, but its genetic aspect has not been studied extensively. Little is known regarding the status of apoptotic factors during the repair process that leads to the occurrence of hip deformity in patients. Therefore, the aim of this study was to analyze major mediators involved in coagulation, inflammation, and apoptotic processes as possible causative factors of Perthes disease. The study cohort consisted of 37 patients. Gene variants of TNF-α, FV, FII, and MTHFR genes were determined by PCR-RFLP, while IL-3 and PAI-1 were genotyped by direct sequencing. The expression level of Bax, Bcl-2, Bcl2L12, Fas and FasL was analyzed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) technique. Our results showed a significantly increased level of expression of pro-apoptotic factor Bax along with significantly higher Bax/Bcl-2 ratio in the patient group. CONCLUSION: The results presented indicate that apoptosis could be one of the factors contributing to the lack of balanced bone remodeling process in Perthes patients.

Association of gene variants in TLR4 and IL-6 genes with Perthes disease.

INTRODUCTION: Perthes disease is idiopathic avascular osteonecrosis of the hip in children, with unknown etiology. Inflammation is present during development of Perthes disease and it is known that this process influences bone remodeling. OBJECTIVE: Since genetic studies related to inflammation have not been performed in Perthes disease so far, the aim of this study was to analyze the association of frequencies of genetic variants of immune response genes, toll-like receptor 4 (TLR4) and interleukin-6 (IL-6), with this disease. METHODS: The study cohort consisted of 37 patients with Perthes disease and 50 healthy controls. Polymorphisms of well described inflammatory mediators: TLR4 (Asp299Gly, Thr39911e) and 11-6 (G-174C, G-597A) were determined by polymerase chain reaction restriction fragment length polymorphism method. Results IL-6 G-174C and G-597A polymorphisms were in complete linkage disequilibrium. A statistically significant increase of heterozygote subjects for IL-6 G-174C/G-597A was found in controls in comparison to Perthes patient group (p = 0.047, OR = 2.49, 95% CI = 1.00-6.21). Also, the patient group for IL-6 G-174C/G-597A polymorphisms was not in Hardy-Weinberg equilibrium. No statistically significant differences were found between patient and control groups for TLR4 analyzed polymorphisms. A stratified analysis by the age at disease onset also did not reveal any significant difference for all analyzed polymorphisms. Conclusion Our study revealed that heterozygote subjects for the IL-6 G-174C/G-597A polymorphisms were significantly overrepresented in the control group than in the Perthes patient group. Consequently, we concluded that children who are heterozygous for these polymorphisms have a lower chance of developing Perthes disease than carriers of both homozygote genotypes.

Evaluation of reversal osteofixation using K-wires in digital replantation.

INTRODUCTION: Modified, reversal technique of fixation in digital replantation using K-wires was analyzed. The results obtained from the standard technique and reversal technique of fixation using K-wires were compared. OBJECTIVE: The aim was to compare the results of osteofixation using K-wires in digital replantation when either standard or reversal, modified technique was used. METHODS: A retrospective study included 103 replanted fingers in 72 patients. The first group included standard fixation using K-wires and the second group included fixation using K-wires, but with a modified technique. Modification consisted of the opposite order of moves during the phalanges fixation compared to the standard technique: first, K-wire was introduced intramedullary in the proximal phalanx and the top of the wire was drawn out through the skin in proximal part of the finger or hand. Second, distal part of the wire was introduced in the phalanx of the amputated part of the finger intramedullary until the wire entered the cortex. RESULTS: Duration of bone healing after digital replantation was shorter in cases where reversal technique was used in comparison with standard technique (7.2 weeks compared to 7.5 weeks). CONCLUSION: The comparison of standard and reversal technique of phalangeal fixation with K-wires in digital replantation shows that both techniques are useful. Reversal technique expands the choice of operative techniques for bone fixation during the replantation. It shows some advantages and enables avoidance of vein injuries.

[Congenital pseudarthrosis of lower leg treated by almost outdated method--case report].

INTRODUCTION: Congenital pseudarthrosis of tibia is a rare congenital deformity with progressive evolution. Treatment is vague and difficult, and many methods have been used--from once mandatory early amputation to contemporary operative (Ilizarov method, free microvascular fibular graft) and adjuvant methods (electrostimulation, biphosphonates, bone morphogenetic protein). We present the usage of once popular method of homologous graft insertion and intramedullary fixation. CASE OUTLINE: This is a case report of male patient with pseudarthrosis involving both crural bones (Boyd type 5), diagnosed in neonatal age. Early conservative treatment was unsuccessful, so child never initiated gait. At the age of three and a half years, operative treatment was applied: resection of pseudarthrosis on both tibia and fibula, and osteoplasty of tibia using cylindric homologous graft and intramedullary fixation with transtarsal Steinman pin, followed by long leg cast immobilization. Pin was removed after ten months, and physical therapy was initiated 1.5 year after surgery, with initial to partial weight bearing and short leg cast throughout another year. Two and a half years after surgery complete union of graft was documented, and then full weight bearing was allowed. At final visit, five years and three months after surgery, shin axis was correct, leg lengths were equal, and child had normal walk with full range of motion. X-ray showed complete union of both tibia and fibula. CONCLUSION: Despite bad prognostic factors (young age, severe deformity), utilization of obsolete and almost forgotten treatment methods can provide excellent result.

Impact of triple pelvic osteotomy on contact stress pressure distribution in the hip joint.

PURPOSE: We studied changes of contact stress distribution in the hip joint after Tonnis triple pelvic osteotomy applied in the treatment of dysplasia and hip joint incongruence in adolescents. METHODS: In a group of 75 patients, 54 (72 %) female, who underwent surgery by triple pelvic osteotomy in adolescence for developmental disorder of the hip and avascular necrosis of the femoral head, a three-dimensional hip joint model was used based on the radiography of the pelvis with hips. The following biomechanical parameters were calculated: resultant hip force normalised to body weight (R/Wb), inclination of the resultant hip force (θ-R), the position of the stress pole (θ), peak contact hip stress (Pmax), and peak contact hip stress normalised to body weight (Pmax/Wb). Gait quality was also assessed. RESULTS: After surgery the Wiberg CE angle was increased by 17.85° (114 %), resultant hip force normalised to body weight (R/Wb) was decreased by 0.107 (3.3 %), the position of the stress pole was shifted medially by 27.59° (63.5 %), and peak contact hip stress normalised to body weight (Pmax/Wb) was decreased by 2249.74 (55.9 %). Waddling gait was reduced from 17 (23.9 %) to four cases (5.6 %). All changes were statistically highly significant (p<0.01). CONCLUSIONS: The effect of Tonnis triple pelvic osteotomy lies in the improvement of stress distribution across the acetabular cartilage of the hip joint, thus slowing down the degenerative damage of the hip joint.

[Conservative treatment of Malgaigne fracture in young female--case report].

INTRODUCTION: Pelvic ring injuries usually result from high-energy trauma, and cranial and abdominal multiple injuries are frequently present. Malgaigne fracture is referred to pelvic ring disruption at two sites, and is often treated surgically for its instability. We present a case of nonoperative treatment of Malgaigne pelvic fracture. CASE OUTLINE: A 17-year-old girl sustained a Malgaigne fracture falling off a horse. After ruling out urgent multiple trauma in local hospital, she was then transferred to Pediatric Orthopedic and Trauma Service at the Institute of Orthopedic Surgery "Banjica" Belgrade, with provisional cutaneous traction of 2 kg applied to her right leg. After the status evaluation, the supracondylar femoral traction was applied for three months, combined with pelvic cradle for first 73 days. Weight of traction was gradually adjusted according to x-ray check-up, ranging from 1-16 kg (1/4 of body weight). Antibiotic prophylaxis was administered for 10 days, and thromboprophylaxis for two months. After the removal of traction, physical therapy was applied and the patient achieved full weight bearing four months after the injury. Treatment outcome was a symmetric and stable pelvic ring, equal leg length, full range of motion in both hip joints and normal walking. CONCLUSION: Traction therapy, combined with gravitational suspension in pelvic cradle, resulted in excellent clinical result. Although significantly longer and more loaded than usual, normal weight bearing and walking were promptly achieved using intensive physical therapy.

Chiari pelvic osteotomy in the treatment of adolescent hip disorders: possibilities, limitations and complications.

Ninety-nine hips treated by the Chiari pelvic osteotomy were included in this study designed as a retrospective review. The group consisted of 36 male and 50 female patients, with mean age of 15.6 years. Each was diagnosed with developmental dysplasia of the hip (DDH) or avascular necrosis of the femoral head--Legg-Calve-Perthes disease (LCP)--and postreduction avascular necrosis (PAN). Five hip parameters (the acetabular angle of Sharp, the center-edge (CE) angle of Wiberg, the percentage of femoral head uncoverage, the acetabular depth ratio, and the Shenton-Menard arch continuity) were evaluated. Functional outcome was assessed according to Harris hip score (HHS) and McKay criteria for clinical evaluation. The postoperative results showed improvement in all the radiographic parameters. The angle of Sharp showed a decrease of 8.62º (p < 0.01). The CE angle of Wiberg showed an increase of 28.76º (p < 0.01), and the uncoverage of the femoral head showed a decrease of 51.51% (p < 0.01). The improvement of HHS was 11.93 (p < 0.05). The patients' satisfaction was indicated by grade 4.1 ± 0.94 and the doctor's satisfaction by grade 3.7 ± 1.16. The Chiari pelvic osteotomy, in spite of the development of biologically better procedures, has retained its position in the treatment of adolescent hip disorders.

Kinesiological characteristics of ankle joint and rearfoot motion.

Kinesiological analysis of tarsal bones provides better understanding of foot disorders, especially in early childhood, when radiography is hindered by delayed ossification of foot bones. Children begin to walk in the age of 9-15 months, with rearfoot inversion only in initial contact phase, while inversion during terminal stance phase is delayed. Adult walking pattern is usually established at six years of age. Talocrural joint axis medial slope shifts during movements depending on the what part of talus comes in contact with maleolli. As a result, plantar flexion includes valgus, and dorsal flexion includes varus inclination. Subtalar joint axis highly varies among individuals: from 200-680 in sagittal and from 40-470 in frontal plane, with impact on coupled lower leg rotation movements around longitudinal axis. Midtarsal joint has two axes, and their position control the rigidity of forefoot and midfoot kinetic chain. Movement planes of tarsal bones strongly influence walking pattern as well as secure foot development.

Clubfoot in children.

Clubfoot, or talipes equinovarus, is a deformity consisting of equinus, varus, and adductus foot deformity. The true etiology of congenital clubfoot is unknown; several theories have been proposed. The pathology of the individual bones contributes to the clubfoot deformity and soft tissue contractures around the ankle and talocalcaneonavicular joint maintains the deformity and involve muscles, tendons, tendon sheaths, ligaments and joint capsules. Various treatment regimens have been proposed, including the use of corrective splinting, taping, and casting. Surgery in clubfoot is indicated for deformities that do not respond to conservative treatment by serial manipulation and casting. Surgery in the treatment of clubfoot must be tailored to the age of the child and to the deformity to be corrected. The main goals of treatment is the painless, functional and anatomical normal foot without need for custom made footwear, and those can be achieved after detailed, indivudial approach with great experience in pediatric orthopedics.

Flatfoot in children.

Foot arches are defined by the position of bones and stabilized by active and passive soft tissue structures. The most significant foot arches are longitudinal, medial and lateral. During lifetime they develop and change, while the most significant disorder represents the flatfoot. During the first two years of life, the flatfoot in full weight bearing position is considered a normal physiological condition, while in later age it represents a deformity requiring additional diagnostics and treatment. The flexible flatfoot is caused by ligamentous laxity, it is mostly pain-free and is treated symptomatically (prescription of adequate shoes and kinesitherapy). The rigid foot is most often caused by bone changes (tarsal coalition, vertical congenital talus) occurring idiopathically or within neuromuscular pathological conditions, with mostly present pain problems. In such cases treatment is also initiated by non-surgical methods, however, some type of surgical treatment is most frequently necessary to be used.

Hallux valgus.

Hallux valgus is a complex deformity of the forefoot. Beside the lateral deviation of the first metatarsophalangeal joint angle exceeding 15-20 degrees and intermetatarsalvarus exceeding 8-9 degrees, it is also characterized by extensive changes of the soft tissue arch, sesamoid mechanism and metatarsocuneiform joint. It occurs almost exclusively in humans wearing shoes. Although in some measure it can be treated non-operatively, by corrective separators and inserts, operative treatment is predominant. There are numerous operative procedures aimed at the correction of the deformity and inducing normal biomechanics of the forefoot. There are seven conceptually different procedures starting from simple bunionectomy, through various soft tissue procedures, metatarsal and phalangeal osteotomies, to resection arthroplasty and metatarsophalangeal arthrodesis. All have clear indications, and none of them has advantages over the others. In accordance with the etiopathogenesis of the disease prevention is easy; wearing comfortable shoes.

Physical treatment of foot deformities in childhood.

During the period of development foot deformities can occur, not only during the growth and development, but also in the later age. The most frequent foot deformity is flatfoot, congenital club foot and hallux valgus. Prior to the decision on surgical treatment of the deformity, whenever possible the patient should be referred for physical therapy that may yield acceptable results in specific treatment phases. The basis of the treatment involves kinesitherapy, application of certain agents (thermotherapy, electrotherapy, ultrasound) and orthosis for maintaining corrections. If such therapy does not yield satisfactory results, the deformity is surgically corrected. After surgical correction, physical procedures can contribute to more rapid recovery and decrease possible complications (pain, edema, complex regional pain syndrome--Mb Sudec), which can follow the surgical correction of the deformity. In addition, the obligatory form of rehabilitation also involves kinesitherapy.

[Femoroacetabular impingement related to Legg-Calvé-Perthes disease].

Femoroacetabular impingement is an undesirable contact between acetabular rim and femoral neck and presents abnormality of proximal femoral part and acetabulum, as well. Two forms may appear: cam impingement and pincer impingement. Femoroacetabular impingement related to Legg-Calvé-Perthes disease may be caused by various reasons, as the consequence of the disease itself, and as the consequence of its treatment. Coxa magna deformity (large femoral head and neck) and coxa brevis deformity (shortened femoral neck) may produce cam femoroacetabular impingement during hip flexion. After the disease, the flattened femoral head (coxa plana) may persist. Chiari pelvic osteotomy is the only treatment option for such femoral head deformity. Acetabular labrum squeezed continuously between the femoral head and the non-articular part of the cut iliac bone lead to cam femoroacetabular impingement, as well. If Salter or triple pelvic osteotomy is used that may cause a very large iatrogenic acetabular retroversion, we can also refer to radial type pincer femoroacetabular impingement. Treatment of Legg-Calvé-Perthes disease should be conducted according to the natural course of the disease and prognosis. Treatment should start on time, well before a crushed femoral head develops, because it is the easiest way to establish hip spherical congruency at the end of treatment. This is the best option to prevent secondary hip arthrosis caused by femoroacetabular impingement or by insufficient head coverage at the end of remodelling. In each case of delayed hip pain, followed by a limited range of movements, femoroacetabular impingement should be taken into consideration, confirmed, and treated by some of the available therapeutic methods.

Triple pelvic osteotomy for the treatment of residual hip dysplasia. Analysis of complications.

The aim of the paper was to present the results achieved with triple pelvic osteotomy in the treatment of residual hip dysplasia, with special interest in identifying recurrences and complications and how to avoid them. 60 patients (76 hips) with developmental dysplasia of the hip (DDH), treated by the triple pelvic osteotomy according to Tönnis and modified by Vladimirov, were included in the study. Hips were evaluated radiologically with the center-edge (CE) angle, break of the Shenton-Menard arch and index of acetabular depth by Heyman-Herndon, and functionally using the Harris Hip Score (HHS). The postoperative results showed an average increase of the CE angle by a mean of 23.5+/-9.28 degrees, with a highly significant difference between the preoperative and final postoperative findings (t-test, t=-20.85, p<0.01). The mean HHS significantly improved (p<0.01). Total complication rate was 13,1%, divided in: 1,3% (one case) of triple nonunion of iliac, pubic and ischial bones, 7,9% (six cases) of double nonunion of pubic and ischial bones, 2,6% (two cases) of peroneal palsy and 1,3% (one case) of infection. In this study the triple pelvic osteotomy showed to be reliable for acetabular dysplasia in adolescent and young adult, alone or in association with proximal femoral osteotomy and/or great trochanter distal advancement.

Does the gestation age of newborn babies influence the ultrasonic assessment of hip condition?

INTRODUCTION: Ultrasound represents a method of examination of hips of newborn babies capable of defining hip condition and distinguishing stable and unstable hips based on morphological elements. It is accepted in a large number of countries as a method of examination of high risk newborns, or as a method of systematic screening. OBJECTIVE: The objective of this study was to investigate correlation between ultrasonically estimated hip maturity and respective gestation maturity both in premature and term-born babies, and to investigate the influence of different delivery types on hips condition. METHODS: In our study 2045 patients, 1141 males and 904 females, were examined in at the Institute of Neonatology over a period of 5 years. The average age was 34.04 gestation weeks. There were significantly more premature (1698 or 83.03%) than term-born babies (347 or 16.97%). Ultrasound hip examination, as a screening method, was carried out according to Graf. It was followed by clinical examination. Results were analyzed by appropriate statistical methods (chi2-test, one-way ANOVA, multifactor ANOVA). RESULTS: The overall frequency of unstable hips was 3.2%, 1.88% in males and 4.87% in females (p<0.05). 96.8% babies had stable hips, out of which 35.21% were mature and 61.59% immature. In the study of the breech presentation, out of 183 babies, unstable hips were found in 1.58% of male cases, and in 10.23% of female cases. CONCLUSION: Clinical screening of developmental dysplasia of the hip is insufficient for early diagnosis and decision about the treatment of premature babies. The high frequency of unstable hip type IIc (risky) and IId (decentralized) in premature babies requires early diagnosis and therapy. Wide swaddling for prematures should be applied up to eight months of age. Gentle manipulation is necessary while nursing and conducting physiotherapy of a premature baby.

Triple pelvic osteotomy in the treatment of hip dysplasia.

INTRODUCTION: Insufficient femoral head coverage is found in a variety of diseases, with acetabular dysplasia as the most frequent disorder and triple pelvic osteotomy as the most recently introduced surgical treatment. OBJECTIVE: This study analyses pre- and postoperative pathoanatomic characteristics of triple in comparison to Salter and Chiari osteotomies, with a logistic regression analysis of outcome predictor and effect explanator factors in relation to the chosen type of operation. METHODS: The study involved 136 adolescents treated with Salter and Chiari osteotomies or a triple pelvic osteotomy at the Institute of Orthopaedic Surgery "Banjica" in Belgrade. The patients were between 10-20 years old at the time of operation. We collected and analyzed data from all the patients: illness history, operative parameters, preoperative and postoperative pathoanatomic data. The data was statistically processed using the statistical software SPSS, defining standard descriptive values, and by using the appropriate tests of analytic statistics: t-test for dependent and independent variables, chi2-test, Fisher's exact test, Wilcoxon's test, parameter correlation, one-way ANOVA, multi-factorial ANOVA and logistic regression, according to the type of the analyzed data and the conditions under which the statistical methods were applied. RESULTS: The average CE angle after triple pelvic osteotomy was 43.5 degrees, more improved than after the Salter osteotomy (33.0 degrees) and Chiari osteotomy (31.4 degrees) (F = 16.822; p < 0.01). Postoperative spherical congruence was also more frequent after the triple osteotomy than after the other two types of operations, and with a high significance. Preoperative painful discomfort was found to be a valid predictor of indications for the triple osteotomy over both Chiari and Salter osteotomies. The valid explanators of effect for the triple osteotomy are: postoperative joint congruence (compared to the Chiari osteotomy) and increase in joint coverage (compared to Salter osteotomy). CONCLUSION: Triple pelvic osteotomy is the method of choice in the management of acetabular dysplasia and other disturbances of hip joint containment in adolescent age.