The role of WNT and IL-1 signaling in osteoarthritis: therapeutic implications for platelet-rich plasma therapy.

Different from inflammatory arthritis, where biologicals and targeted synthetic molecules have revolutionized the disease course, no drug has demonstrated a disease modifying activity in osteoarthritis, which remains one of the most common causes of disability and chronic pain worldwide. The pharmacological therapy of osteoarthritis is mainly directed towards symptom and pain relief, and joint replacement is still the only curative strategy. Elucidating the disease pathophysiology is essential to understand which mechanisms can be targeted by innovative therapies. It has extensively been demonstrated that aberrant WNT and IL-1 signaling pathways are responsible for cartilage degeneration, impaired chondrocyte metabolism and differentiation, increased extracellular matrix degradation, and altered subchondral bone homeostasis. Platelet-rich plasma is an autologous blood derivative containing a concentration of platelets that is much higher than the whole blood counterpart and has shown promising results in the treatment of early knee osteoarthritis. Among the proposed mechanisms, the modulation of WNT and IL-1 pathways is of paramount importance and is herein reviewed in light of the proposed regenerative approaches.

Ultrasound-guided injection of platelet-rich plasma or cord blood platelet-rich plasma in nonunion: a randomized controlled trial.

Aim: To compare the ability of autologous platelet-rich plasma (PRP) and cord blood PRP (PRPc) to accelerate bone healing. Patients & methods: 71 patients with mechanically stable nonunion were treated weekly (3 consecutive weeks) with ultrasound-guided percutaneous injections of PRP or PRPc in a controlled randomized clinical trial. The primary outcome was healing (12 months) and secondary outcomes were radiological evolution (2 and 6 months) and changes in pain intensity (6 months). Results & conclusion: Bone consolidation was assessed over time without significant differences between PRP and PRPc treatment. In patients with persistent nonunion, pain perception decreased more after PRP treatment. PRPc appears to be a valid alternative when specific clinical conditions suggest avoiding the use of autologous blood products.

Although the regenerative capacity of bone tissue is well recognized, the fracture repair process may be impaired by unfavorable conditions resulting in delayed union or complete nonunion. In this scenario, the use of autologous blood derivates to accelerate bone healing has been proposed. The aim of this study was to compare the therapeutic efficacy of autologous platelet-rich plasma (PRP) and cord blood PRP (PRPc) in bone nonunion. PRPc contains high levels of cytokines and growth factors, has low immunogenicity and can be successfully stored until use. This study verified that bone consolidation was similar in PRP and PRPc treatments, thus supporting PRPc as a valid therapeutic option when clinical conditions discourage the use of autologous blood derivates.

Fresh Osteochondral Allograft Transplantation in Osteochondritis Dissecans in the Knee Joint.

Osteochondritis dissecans (OCD) is a chronic and painful joint condition that can occur from childhood through to adult life. Microtrauma, vascular insufficiency, or abnormal endochondral ossification are the most common causes of OCD. Reconstructive techniques for OCD of the knee are typically necessary when either non-operative or reparative/regenerative operative treatments fail, or when the OCD is irreversible. To analyze the clinical outcomes and failure rates of fresh osteochondral allograft transplantation (FOCA) used as a reconstructive strategy in OCD patients, an in-depth search was carried out on the PubMed, Scopus, and Web of Science databases concerning the existing evidence related to the use of FOCA for OCD patients in the knee joint. A total of 646 studies were found through the search and 2 studies were added after a cross-referenced examination of the articles within the bibliography. Six studies with a total of 303 OCD lesions treated with FOCA, with a mean follow-up of 6.3 years, were included. Although a limited number of low-level evidence studies on this topic are available in previous research, satisfactory clinical results and survival rates of the reconstruction are reported. However, to better define the real advantages of FOCA in the healing process of OCD lesions, comparative studies with different techniques are needed.

Randomised, double-blind comparison of a fixed co-formulation of intra-articular polynucleotides and hyaluronic acid versus hyaluronic acid alone in the treatment of knee osteoarthritis: two-year follow-up.

BACKGROUND: A first-year interim analysis of this two-year study suggested that intra-articular injections of highly purified, natural-origin polynucleotides and hyaluronic acid (HA) as a fixed combination (PNHA) might improve knee function and joint pain more effectively than HA alone in patients with knee osteoarthritis (OA). The purpose of the second-year analysis herein described was to verify whether the first-year interim outcomes persist over the whole two-year period. METHODS: Randomised, double-blind, HA-controlled clinical trial in 100 knee OA patients (98 randomised, 79 completing the study) in a high-specialisation tertiary care setting. The hypothesised difference of efficacy between PNHA and HA for the original sample size estimate is 20%. Treatment cycle: three intra-articular knee injections of either PNHA or HA, at baseline and weekly for two weeks. EVALUATIONS: Western Ontario and McMaster Universities (WOMAC) score and Knee Society Score (KSS) as, respectively, primary and secondary endpoints, evaluated at baseline and after 2, 6, 12, and 24 months; synovial fluid levels of mediators (at baseline and the end of the treatment cycle). Adverse effects investigated at each control visit. STATISTICAL ANALYSIS: Kruskal-Wallis test for independent samples (nonparametric one-way analysis of variance) after correction of means for age, Body Mass Index and Kellgren-Lawrence grade. If significant, pairwise post-hoc Sidak multiple comparisons. RESULTS: KSS total score and KSS pain item: significant improvement in both groups, with significantly more pain improvement in patients treated with PNHA (2-point reduction) than HA (1-point reduction). Both groups experienced significant long-term reductions in WOMAC total scores: significantly stronger in PNHA-treated patients after 24 months with a steady difference of 16% favouring PNHA in WOMAC pain subscore. No clinically significant adverse events in either group. CONCLUSIONS: The outcomes of the 2-year study confirmed that a short cycle of intra-articular treatment (3 weekly double-blind injections) with polynucleotides (long-acting viscosupplementation properties, chondrocyte activation, pain-relieving properties) in fixed combination with high molecular weight hyaluronic acid is more effective in improving knee function and pain in knee OA patients than HA alone. PNHA may be elective for viscosupplementation in knee OA patients with fastidious and resistant pain and worsening disease. TRIAL REGISTRATION: NCT02417610 . Registration, 15/04/2015. ClinicalTrials.gov database link.

Bone marrow aspirate concentrate/platelet-rich fibrin augmentation accelerates healing of aseptic upper limb nonunions.

INTRODUCTION: Nonunions remain a significant burden in orthopedics, often afflicting young males of working age. Positive findings have been published using bone marrow aspirate concentrate (BMAC) and platelet-rich fibrin (PRF) for the treatment augmentation of lower limb nonunions. The aim of this study was to investigate if the treatment augmentation with BMAC and PRF can also accelerate the healing of nonunions of the upper limb. MATERIALS AND METHODS: Sixty-eight patients (45 men, 23 women) affected by 75 nonunions of long bones of the upper limb were treated and divided into two groups. The first series was treated with standard surgery alone (group A); afterwards, the second series benefited from standard surgery with the addition of BMAC and PRF applied on lyophilized bone chips. Nonunions were classified radiographically according to the Weber-Cech method and prognostically using the Calori and Moghaddam scores. All patients were radiographically assessed at 1.5, 3, 6, 12, and 24 months of follow-up. RESULTS: Baseline demographic characteristics did not present differences between groups. No differences were documented in terms of complications (two in group A and three in group B). Significant differences were instead documented in terms of healing time. The first healing signs were observed 1.5 months after surgery in 90.7% of patients in group B and 34.4% of group A (p < 0.0005). At 1.5, 3, 6, and 12 months, a higher radiographic score was found for group B (all p < 0.0005), while no difference was found at final follow-up of 24 months (90.6% of group A and 97.7% of group B achieved radiological healing). Faster healing with BMAC/PRF augmentation was confirmed for all bones, as well as for the subgroup of patients affected by atrophic nonunions (p = 0.001). CONCLUSION: This study showed the benefits of restoring both mechanical and biological aspects when addressing nonunions of the long bones of the upper limb. In particular, the association of BMAC and PRF to lyophilized bone chips was safe and able to accelerate healing time. These good results were confirmed for humerus, radius, and ulna sites, as well as for challenging atrophic nonunions of the upper limb.

Cell-based Assay System for Predicting Bone Regeneration in Patient Affected by Aseptic Nonunion and Treated with Platelet Rich Fibrin.

BACKGROUND: Regenerative strategies based on the use of platelet concentrates as an autologous source of growth factors (GF) has been proposed to promote the healing of long bone nonunions. However, the relatively high failure rate stimulates interest in growing knowledge and developing solutions to obtain the best results from the regenerative approach. OBJECTIVE: In this study we evaluated whether a cell-based assay system could be able to recognize patients who will benefit or not from the use of autologous platelet preparations. METHOD: The autologous serum was used in culture medium to promote the osteogenic differentiation of normal bone-marrow stromal cells (BMSC). Blood samples were collected from 16 patients affected by aseptic long bone nonunion who were candidates to the treatment with autologous platelet-rich fibrin. The osteoinductive effect was detected by measuring the BMSC proliferation, the mineralization activity, and the expression of bone-related genes. Serum level of basic fibroblast growth factor (bFGF) was considered as a representative marker of the delivery of osteogenic GFs from platelets. Laboratory results were related to the characteristics of the disease before the treatment and to the outcome at 12 months. RESULTS: Serum samples from "good responders" showed significantly higher levels of bFGF and were able to induce a significantly higher proliferation of BMSC, while no significant differences were observed in terms of osteoblast differentiation. CONCLUSION: BMSC-based assay could be a useful tool to recognize patients who have a low probability to benefit from the use of autologous platelet concentrate to promote the healing of long bone nonunion.

Infiltrative therapy as conservative treatment in hip osteoarthritis: a literature review.

Osteoarthritis (OA) is a very common disease, its prevalence increases with age and is a frequent cause of disability.Osteoarthritis is characterised by joint pain, stiffness and loss of range of motion. Overall, as many as 40% of those aged over 65 years in the community may have symptomatic OA of the knee or hip (1). OA results from a complex interaction of biomechanical and biochemical factors and is characterised by cartilage disruption and hypertrophy of bone. Intraarticular proinflammatory cytokines and proteinases in OA interfere with the synthesis of hyaluronic acid (HA), a complex glycosaminoglycan composed of repeated disaccharide units to form a linear polymer, resulting in an HA with a significantly reduced molecular weight and a reduction in synovial fluid viscoelasticity (2-3). Loss of normal characteristics of HA leads to the degradation of the articular cartilage and the disruption of the mechanical and homeostasis of the joint.Several pharmaceutical approaches, such as analgesics, non steroidal antiinflammatory drugs, COX-2 inhibitors and steroids, have been proposed (4), with the aim of reducing pain and maintaining and/or improving joint function. However, none of these options has shown to delay the progression of osteoarthritis or reverse joint damage.Infiltrative hip therapy involves injecting into the joint the drugs or medicinal substances that are used primarily to control the symptoms of the disease, such as pain and functional limitation.The aim of this review is to analyse existing infiltrative alternatives for hip osteoarthritis, and describe our experience.

The role of arthroscopy in the treatment of groin pain after total hip arthroplasty: our experience.

AIM: The purpose of the study was to present our arthroscopic surgical technique and the results in patient with pain after a hip replacement. METHODS: Between November 2009 and September 2011, 35 patients with groin pain after total hip arthroplasty (THA) were treated arthroscopically. The patients underwent a preoperative examination consisting in careful history, physical examination, laboratory evaluation, diagnostic evaluation using x-rays and pelvis CT scans. In patients for whom the clinical picture suggested iliopsoas tendonitis, we also performed injection of local anaesthetic on the iliopsoas tendon sheath. All the patients were positioned in the supine decubitus position with traction applied, using 2 arthroscopic portals (AL, MID-A). An extensive debridement of adhesions, periprosthetic tissue and neocapsula were performed; when there were signs of iliopsoas impingement, a transcapsular tenotomy was performed according to Wettstein technique. RESULTS: The average age was 57 (29-77) years old. The average time to onset of symptoms was 10.8 (5-15) months after THA. The average preoperative Harris Hip Score (HHS) was 44.1 (range 32-56). The average preoperative Medical Research Council (MRC) scale for muscle strenght was 3.27 (range 3-4). After 24 months of follow-up patients show an average HHS of 75.73 (range 50-91). Patients who underwent iliopsoas release show a postoperative HHS of 83.28 (range 61-91). The average postoperative MRC scale was 4.45. CONCLUSIONS: Hip arthroscopy in treatment of reactive synovitis and adhesions shows good results according to literature. Hip arthroscopy in treatment of anterior iliopsoas impingement is the most useful instrument, being less invasive than the classic open technique.

Ultrasound-Guided Injection of Platelet-Rich Plasma and Hyaluronic Acid, Separately and in Combination, for Hip Osteoarthritis: A Randomized Controlled Study.

BACKGROUND: The effectiveness of intra-articular platelet-rich plasma (PRP) injections has been evaluated in knee chondroplasty and osteoarthritis (OA); however, little evidence of its efficacy in hip OA exists. PURPOSE: To compare the therapeutic efficacy of autologous PRP, hyaluronic acid (HA), or a combination of both (PRP+HA) in hip OA. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients aged between 18 and 65 years who were treated with outpatient surgery and who had hip OA and pain intensity at baseline of >20 on a 100-mm visual analog scale (VAS) were recruited for this study. Exclusion criteria were extensive surgery; presence of excessive deformities; or rheumatic, infective, cardiovascular, or immune system disorders. The primary outcome measure was a change in pain intensity as assessed by the VAS at 2, 6, and 12 months after treatment. Secondary outcome measures were the Harris Hip Score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and concentration of growth factors in PRP and their correlation with clinical outcomes. Clinical outcomes were evaluated by assessors and collectors blinded to the type of treatment administered. RESULTS: A total of 111 patients were randomly assigned to 3 groups and received 3 weekly injections of either PRP (44 patients), PRP+HA (31 patients), or HA (36 patients). At all follow-ups, the PRP group had the lowest VAS scores. In particular, at 6-month follow-up, the mean VAS score was 21 (95% CI, 15-28) in the PRP group, 35 (95% CI, 26-45) in the PRP+HA group, and 44 (95% CI, 36-52) in the HA group (P < .0005 [PRP vs HA] and P = .007 [PRP vs PRP+HA]; F = 0.663). The WOMAC score of the PRP group was significantly better at 2-month follow-up (mean, 73; 95% CI, 68-78) and 6-month follow-up (mean, 72; 95% CI, 67-76) but not at 12-month follow-up. A significant, "moderate" correlation was found between interleukin-10 and variations of the VAS score (r = 0.392; P = .040). Significant improvements were achieved in reducing pain and ameliorating quality of life and functional recovery. CONCLUSION: Results indicated that intra-articular PRP injections offer a significant clinical improvement in patients with hip OA without relevant side effects. The benefit was significantly more stable up to 12 months as compared with the other tested treatments. The addition of PRP+HA did not lead to a significant improvement in pain symptoms.

Prospective multi-centre study on a composite ceramic femoral component in total knee arthroplasty: Five-year clinical and radiological outcomes.

BACKGROUND: Enhanced wear resistance of ceramics in general and improved mechanical characteristics of composite ceramics in terms of strength and resistance meet the demands for application in TKA. The aim of this prospective international multi-centre study was to evaluate the 5-year clinical and radiological outcomes of an unconstrained TKA with a composite ceramic femoral component. METHODS: A total of 107 patients (109 knees) underwent TKA with the MULTIGEN-PLUS Ceramic Knee at seven centres in three European countries. Clinical and radiological assessments were performed preoperatively and postoperatively at 3, 12, 24 and 60 months, using HSS, WOMAC, SF-36 and standardised radiographs. RESULTS: Mean HSS and WOMAC increased significantly from 55.1±11.5 (21-83) and 48.1±16.6 (3-90) preoperatively to 85.6±9.6 (49-98) and 73.3±20.4 (17-100) at 60 months. Mean SF-36 showed significant improvements in patients' quality of life (49.1±17.6 (12-96) preoperatively versus 67.7±23.1 (12-100) at 60 months). Non-progressive radiolucent lines (<1 mm) were observed around the femoral component in four cases. Neither implant migration nor loosening were registered. Kaplan-Meier survivorship was 96.0% at 60 months (92.1-100%, CI 95%). CONCLUSIONS: Five-year implant survival rate of the ceramic knee is comparable to other metallic and ceramic unconstrained TKA systems. Although the assessment of long-term implant survivorship is still pending, the ceramic implants represent a promising solution for patients with allergies against metallic components and furthermore for the general osteoarthritis population due to enhanced wear resistance.

Ceramic femoral components in total knee arthroplasty - two year follow-up results of an international prospective multi-centre study.

BACKGROUND: Total knee arthroplasty can be considered as a reliable surgical procedure with a good long-term clinical result. However, implant failure due to particle induced aseptic loosening as well as the aspect of hypersensitivity to metal ions still remains an emerging issue. METHODS: The purpose of this prospective international multi-centre study was to evaluate the clinical and radiological outcomes and the reliability of the unconstrained Multigen Plus Total Knee System with a new BIOLOX® delta ceramic femoral component. Cemented total knee arthroplasty was performed on 108 patients (110 knees) at seven hospitals in three countries. Clinical and radiological evaluations were performed preoperatively, and after 3, 12 and 24 months postoperatively using the HSS-, WOMAC-, SF-36-score and standardised X-rays. RESULTS: The mean preoperative HSS-Score amounted to 55.5 ± 11.5 points and improved significantly in all postoperative evaluations (85.7 ± 11.7 points at 24 months). Furthermore, improvements in WOMAC- and SF-36-score were evaluated as significant at all points of evaluation. Radiolucent lines around the femoral ceramic component at 24 months were found in four cases. Progression of radiolucent lines was not seen and no implant loosening was observed. During the 24 month follow-up eight patients underwent subsequent surgery due to reasons unrelated to the implant material. CONCLUSIONS: The observed clinical and radiological results are encouraging for a long-term survival of the ceramic femoral component. Therefore, ceramic implants could be a promising solution not only for patients with allergies against metallic implant materials, but also for the osteoarthritic knee joint. Long-term follow-up is necessary to draw conclusions regarding the superiority of the ceramic knee implants concerning in vivo wear and long-term survivorship.

Relevance of deep decortication and vascularization in a case of post-traumatic femoral non-union treated with grafts, platelet gel and bone marrow stromal cells.

PURPOSE: A male patient suffering from non-union of the femoral diaphysis after a traumatic fracture was treated with deep decortication and grafted with lyophilized bone, platelet gel (PG) and autologous bone marrow stromal cells (BMSCs). After 40 days from surgery, he was re-operated, due to fracture secondary displacement, caused by inappropriate load during sports activity. In addition to radiographs, two bone biopsies were retrieved: this allowed for a histological evaluation of the early response of host bone to the graft. To our knowledge, there is no report describing such early tissue response. METHODS: A clinical-radiographic evaluation of the patient and a histomorphometric analysis of the bone biopsies were performed. RESULTS: An early reparative bone formation was observed adjacent to the osteointegrated graft. Non-resorbed bone chips and large islands of non-vital bone particles, surrounded by fibrous tissue, were observed in a zone of sclerotic diaphyseal bone, that is the process was delayed despite decortication. CONCLUSIONS: These findings support the concept, until now evidenced only by imaging, that bone chips added with PG and BMSCs are effective in shortening the healing time in fracture non-union. The clinical relevance of deep decortication and vascularization is emphasized. LEVEL OF EVIDENCE: Therapeutic studies-investigating the results of treatment, Level V.

Total hip arthroplasty after excision arthroplasty: indications and limits.

We reviewed performed a retrospective review of our series of excision arthroplasty patients and identified 16 patients who had undergone the procedure for sepsis, and who we had subsequently subjected to revision to a total hip arthroplasty (THA). Mean follow-up was 96 +/- 15 months. There was a significant reduction in limb length discrepancy and a marked improvement in walking capability. Range of movement improved most in patients under 65 years of age. Patient selection is critical, because THA after excision arthroplasty is complex, and may have less satisfactory results primary surgery.

Total hip arthroplasty with shortening osteotomy in congenital major hip dislocation sequelae.

We retrospectively evaluated the postoperative results of total hip arthroplasty (THA) in patients presenting with Crowe group IV dislocated hips. Overall, results were compared with regard to the type of osteotomy performed (Z or oblique) to define the correct indications for surgical technique and choice of prosthetic implant. Thirty-three subtrochanteric shortening and derotational osteotomies in primary THA were performed in 26 patients secondary to congenital hip dislocation. A Z osteotomy was performed in 14 cases and an oblique osteotomy in 19. The surgical approach was direct lateral, and surgery was aimed at restoring the anatomic hip center. Femoral and acetabular fixation was uncemented. The most used stem was the S-ROM (DePuy, Leeds, United Kingdom), and the couplings used were ceramic-ceramic (7 cases), ceramic-polyethylene (3 cases), metal-polyethylene (15 cases), and metal-metal (3 cases). Mean follow-up was 88±45 months. According to the Merle D'Aubigné score, the overall clinical results were good in 23 cases, satisfactory in 6, and fair in 4. Union of the osteotomy occurred in 97% of cases, and the mean time required for osteotomy union was 6±2 months without significant differences between Z and oblique osteotomies. At last follow-up, there was loosening of 1 cup and 1 stem, and revision was necessary. Twelve percent of patients experienced postoperative dislocation and 9% developed neuropraxia of the femoral nerve. The clinical and radiological results were similar in both groups, with a high rate of pain relief, an improvement in limb-length discrepancy, and reduced limping, leading to a smaller or no insole. Currently, the more complex Z osteotomy has been abandoned, because a modular stem prosthesis with metaphyseal sleeve allows the oblique osteotomy to be used with an easier and shorter surgical procedure.

Two stage hip revision in periprosthetic infection: results of 41 cases.

BACKGROUND: two-stage revision is considered the best treatment approach for the eradication of chronic joint infection. We report the outcome of 41 consecutive patients with infected hip prostheses, treated between 2000 and 2005, with two-stage revision using an antibiotic-loaded cement spacer. METHODS: Patients underwent a treatment protocol which included clinical and radiographic evaluation, laboratory investigations, hip aspiration, 99mTc-MDP and 99mTc-leukocyte-labeled scintigraphy and intraoperative assessment. All patients were diagnosed with a late chronic infection and classified as B-host according to the Cierny-Mader classification system. 9 patients out of 41 (22%) required a second interim treatment period, with exchange of the spacer. The proportion of methicillin-resistant Staphylococcus was similar between the one-spacer group and two-spacer group (28% vs 33%), whereas the proportion of patients with three or more risk factors was significantly higher in the two-spacer group than in the one-spacer group (28% vs 55%, respectively). RESULTS: Forty patients had final reimplantation, one patient had a resection arthroplasty. At an average follow-up of 5.3 years no recurrence of infection occurred. The average post-operative Harris hip score improved from 41 to 80. CONCLUSIONS: In the treatment of two-stage revision arthroplasty the adherence to the protocol proved to be effective for infection eradication and final reimplantation.

Neurofibromatosis with unilateral lower limb gigantism.

The case of a 3-year-old child diagnosed with Type 1 neurofibromatosis is presented, showing pigmented birthmarks and gigantism of the left lower limb associated with the presence of multiple neurofibromas. Increased bone growth appears to be the direct or indirect consequence of a still undefined paracrine effect of nerve tumor cells.

Effects of pulsed electromagnetic stimulation on patients undergoing hip revision prostheses: a randomized prospective double-blind study.

In this prospective, randomized, double-blind study, the effect of Pulsed Electromagnetic Fields (PEMFs) was investigated in 30 subjects undergoing hip revision using the Wagner SL stem. The subjects were treated for 6 h/day up to 90 days after revision. Study end points were assessed clinically by the functional scale of Merle D'Aubigné and instrumentally by Dual-Energy X-ray Absorptiometry (DXA) at the Gruen zones. Subject improvement according to Merle D'Aubigné scale was higher (P < 0.05) in subjects undergoing active stimulation compared to placebo. In analyzing the DXA findings, we subtracted for each area the postoperative bone mineral density (BMD) values from those measured at 90 days and we considered all results above 3.5% as responders. There were no significant differences in the average BMD values at each Gruen zone between the two groups both postoperatively and at 90 days investigation. In Gruen zones 5 and 6, corresponding to the medial cortex, we observed six responders (40%) in both areas in the control group, while in the stimulated group we observed 14 (93%) and 10 (66%) responders, respectively (both P < 0.05). This study showed that PEMF treatment aids clinical recovery and bone stock restoration.