Spinal fusion procedures in the adult and young population: a systematic review on allogenic bone and synthetic grafts when compared to autologous bone.

This systematic review aims to compare clinical evidences related to autologous iliac crest bone graft (ICBG) and non-ICBG (local bone) with allografts and synthetic grafts for spinal fusion procedures in adult and young patients. A systematic search was carried out in three databases (PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials) to identify clinical studies in the last 10 years. The initial search retrieved 1085 studies, of which 24 were recognized eligible for the review. Twelve studies (4 RCTs, 5 prospective, 3 retrospective) were focused on lumbar spine, 9 (2 RCTs, 2 prospective, 4 retrospective, 1 case-series) on cervical spine and 3 (1 RCT, 2 retrospective) on spinal fusion procedures in young patients. Calcium phosphate ceramics, allografts, bioglasses, composites and polymers have been clinically investigated as substitutes of autologous bone in spinal fusion procedures. Of the 24 studies included in this review, only 1 RCT on cervical spine was classified with high level of evidence (Class I) and showed low risk of bias. This RCT demonstrated the safety and efficacy of the proposed treatment, a composite bone substitute, that results in similar and on some metrics superior outcomes compared with local autograft bone. Almost all other studies showed moderately or, more often, high incidence of bias (Class III), thus preventing ultimate conclusion on the hypothesized beneficial effects of allografts and synthetic grafts. This review suggests that users of allografts and synthetic grafting should carefully consider the scientific evidence concerning efficacy and safety of these bone substitutes, in order to select the best option for patient undergoing spinal fusion procedures.

BIOPHYSICAL STIMULATION FOR NONUNIONS.

Nonunions account for 5-10% on the total number of fractures. Biophysical stimulation is a non-surgical, conservative, frequently used therapy in nonunions and a greater efficacy has been demonstrated for pulsed electromagnetic fields (PEMF). The mechanisms of action of PEMF at cellular and molecular levels are still under debate and no dose-response study is available. Moreover, the vast majority of in vitro studies were conducted on healthy cells. The primary aim of the research was to investigate the capacity of PEMF with different exposure times to stimulate the osteogenic process in cells from the callus of a nonunion patient. Another important objective was the characterization of nonunion cells in terms of clonogenicity, cluster of differentiation expression and the tri-lineage differentiation capacity. Overall, the results indicated the presence of osteochondroprogenitor cells in the callus of a nonunion, with an impairment in the osteogenic differentiation process. PEMF may enhance cell viability, the formation of osteoid matrix and accelerate the process of osteogenic differentiation. BMP-4 production, TIMP1 and TIMP2 expression were influenced, as well as VEGFA, whose early upregulation may account for a possible improvement in both the osteogenic and vasculogenic processes. In conclusion, even with some discussed limitations, these preliminary data showed the presence of a multipotent progenitor population and suggested some hints of the effect of PEMF on nonunion cells.

Long-term in vivo experimental investigations on magnesium doped hydroxyapatite bone substitutes.

Despite several efforts to find suitable alternatives to autologous bone, no bone substitute currently available provides the same characteristics and properties. Nevertheless, among the wide range of materials proposed as bone substitutes, calcium phosphate materials represent the most promising category and the present study is aimed at improving the knowledge on non-stoichiometric magnesium-doped hydroxyapatite substitutes (Mg-HA), tested in two different formulations: Mg-HA Putty and Mg-HA Granules. These bone substitutes were implanted bilaterally into iliac crest bone defects in healthy sheep and comparative histological, histomorphometric, microhardness and ultrastructural assessments were performed 9, 12, 18 and 24 months after surgery to elucidate bone tissue apposition, mineralization and material degradation in vivo. The results confirmed that the biomimetic bone substitutes provide a histocompatible and osteoconductive structural support, during the bone formation process, and give essential information about the in vivo resorption process and biological behavior of biomimetic bone substitutes.

Prospects on the Potential In Vitro Regenerative Features of Mechanically Treated-Adipose Tissue for Osteoarthritis Care.

Gathering a better grasp on the adipose stromal vascular fraction (SVF) is demanding among clinicians for osteoarthritis (OA) care because of its promising but multifaceted clinical outcomes. The aim of this preclinical in vitro study was to test whether the mechanical approach with Hy-Tissue SVF system, a class IIa CE marked device of adipose tissue micro-fragmentation, influences the biological features and functions of SVF. We compared mechanical generated-SVF (mSVF) with the enzymatic generated-SVF (eSVF) by testing cell survival, phenotype, differentiation, and paracrine properties using ELISA assays. Both adipose SVF showed 80% viable cells and enrichment for CD-44 marker. The mSVF product preserved the functions of cell populations within the adipose tissue; however, it displayed lowered nucleated cell recovery and CFU-F than eSVF. As for multipotency, mSVF and eSVF showed similar differentiation commitment for osteochondral lineages. Both adipose SVF exhibited an increased release of VEGF, HGF, IGF-1 and PDGF-bb, involved in pathways mediating osteochondral repair and cell migration. Both mSVF and eSVF also displayed high release for the anti-inflammatory cytokine IL-10. After in vitro culture, supernatants from both mSVF and eSVF groups showed a low release of cytokines except for IL-10, thereby giving evidence of functional changes after culture expansion. In this study, mSVF showed active cell populations in the adipose tissue comparable to eSVF with excellent survival, differentiation and paracrine properties under a new mechanical adipose tissue micro-fragmentation system; thereby suggesting its potential use as a minimally invasive technique for OA treatment.

Current Trends in the Evaluation of Osteochondral Lesion Treatments: Histology, Histomorphometry, and Biomechanics in Preclinical Models.

Osteochondral lesions (OCs) are typically of traumatic origins but are also caused by degenerative conditions, in primis osteoarthritis (OA). On the other side, OC lesions themselves, getting worse over time, can lead to OA, indicating that chondral and OC defects represent a risk factor for the onset of the pathology. Many animal models have been set up for years for the study of OC regeneration, being successfully employed to test different treatment strategies, from biomaterials and cells to physical and biological adjuvant therapies. These studies rely on a plethora of post-explant investigations ranging from histological and histomorphometric analyses to biomechanical ones. The present review aims to analyze the methods employed for the evaluation of OC treatments in each animal model by screening literature data within the last 10 years. According to the selected research criteria performed in two databases, 60 works were included. Data revealed that lapine (50% of studies) and ovine (23% of studies) models are predominant, and knee joints are the most used anatomical locations for creating OC defects. Analyses are mostly conducted on paraffin-embedded samples in order to perform histological/histomorphometric analyses by applying semiquantitative scoring systems and on fresh samples in order to perform biomechanical investigations by indentation tests on articular cartilage. Instead, a great heterogeneity is pointed out in terms of OC defect dimensions and animal's age. The choice of experimental times is generally adequate for the animal models adopted, although few studies adopt very long experimental times. Improvements in data reporting and in standardization of protocols would be desirable for a better comparison of results and for ethical reasons related to appropriate and successful animal experimentation.

Use of Antibiotic Loaded Biomaterials for the Management of Bone Prosthesis Infections: Rationale and Limits.

BACKGROUND: Periprosthetic joint infection still represents a challenging issue for the orthopedic community. In the United States approximately a million joint arthroplasties are performed each year, with infection rates ranging from 1 to 2%: revisions has significant implications on health care costs and appropriate resource management. The use of locally applied antibiotics as a prophylaxis measure or as a component of the therapeutic approach in primary or revision surgery is finalized at eliminating any microorganism and strengthening the effectiveness of systemic therapy. OBJECTIVE: The present review of clinical and preclinical in vivo studies tried to identify advantages and limitations of the materials used in the clinical orthopedic practice and discuss developed biomaterials, innovative therapeutic approaches or strategies to release antibiotics in the infected environment. METHODS: A systematic search was carried out by two independent observers in two databases (www.pubmed.com and www.scopus.com) in order to identify pre-clinical and clinical reports in the last 10 years. RESULTS: 71 papers were recognized eligible: 15 articles were clinical studies and 56 in vivo studies. CONCLUSION: Polymethylmethacrylate was the pioneer biomaterial used to manage infections after total joint replacement. Despite its widespread use, several issues still remain debated: the methods to combine materials and antibiotics, the choice of antibiotics, releasing kinetics and antibiotics efficacy. In the last years, the interest was directed towards the selection of different antibiotics, loaded in association with more than only one class and biomaterials with special focus on delivery systems as implant surface coatings, hydrogels, ceramics, micro-carriers, microspheres or nanoparticles.

Brillouin micro-spectroscopy of subchondral, trabecular bone and articular cartilage of the human femoral head.

Brillouin micro-spectroscopy is applied for investigating the mechanical properties of bone and cartilage tissues of a human femoral head. Distinctive mechanical properties of the cartilage surface, subchondral and trabecular bone are reported, with marked heterogeneities at both micrometric and millimetric length scales. A ubiquitous soft component is reported for the first time, characterized by a longitudinal modulus of about 4.3 GPa, possibly related to the amorphous phase of the bone. This phase is mixed, at micrometric scales, with a harder component, ascribed to mineralized collagen fibrils, characterized by a longitudinal modulus ranging between 16 and 25 GPa.

Pulsed electromagnetic fields and platelet rich plasma alone and combined for the treatment of wear-mediated periprosthetic osteolysis: An in vivo study.

Wear-mediated osteolysis is a common complication occurring around implanted prosthesis, which ultimately leads to bone loss with mechanical instability and the need for surgical revision. At the moment, revision surgery is the only effective treatment. The aim of this study was to assess the efficacy of pulsed electromagnetic fields (PEMFs) and platelet rich plasma (PRP), alone and in association, in a clinically relevant in vivo model of periprosthetic osteolysis. Titanium alloy pins were implanted intramedullary in distal femurs of male inbred rats and, after osseointegration, polyethylene particles were injected intra-articularly to induce osteolysis. Animals were divided in four groups of treatment: PEMFs, PRP, PEMFs + PRP and no treatment. Microtomography was performed during the course of experiments to monitor bone stock and microarchitecture. Histology, histomorphometry, immunohistochemistry and biomechanics were evaluated after treatments. Biophysical and biological stimulations significantly enhanced bone to implant contact, bone volume and bone microhardness and reduced fibrous capsule formation and the number of osteoclasts around implants. Among treatments, PEMFs alone and in association with PRP exerted better results than PRP alone. Present data suggest that biophysical stimulation, with or without the enrichment with platelet derived growth factors, might be a safe, mini-invasive and conservative therapy for counteracting osteolysis and prompting bone formation around implants. STATEMENT OF SIGNIFICANCE: Pulsed electromagnetic fields (PEMFs) and platelet rich plasma (PRP) show anabolic and anti-inflammatory effects and they are already been used in clinical practice, but separately. To date, there are no preclinical in vivo studies evaluating their combined efficacy in periprosthetic osteolysis, in bone tissue microarchitecture and in biomechanics. The aim of the present study was to evaluate the effects of PEMFs and PRP in vivo, when administered individually and in combination in the treatment of periprosthetic wear mediated ostelysis, and in restoring the osteogenetic properties of perimplant bone tissue and its biomechanical competence. The combination of PEMFs and PRP could be employed for counteracting the ostelysis process in a conservative and non surgical manner.

In vitro and in vivo behaviour of biodegradable and injectable PLA/PGA copolymers related to different matrices.

This study comparatively investigates the in vitro and in vivo behavior of injectable polymeric materials for the treatment of bone defects. The tested materials were three injectable and biodegradable PLA/PGA 50/50 copolymers dispersed in different matrices: Fisograft-gel (GEL) was dispersed in an aqueous matrix of poly-ethyl-glycole (PEG); Slurry2 (SL2) was dispersed in an aqueous matrix of PEG and dextran; and Slurry6 (SL6) was dispersed in a 3% agarose matrix. The biological characterization of these materials was studied by in vitro and in vivo tests: the in vitro test assessed the cellular response in terms of viability, differentiation and synthetic activity, while the in vivo test evaluated the healing capacity of bone defects treated with these biomaterials. GEL and SL2 induced a similar response for viability and differentiation of MG63 osteoblast-like cells after a 7-day culture, while SL6 caused a higher production of both interleukin-6 and type I collagen. Since the results showed that the materials were biocompatible and not cytotoxic in vitro, the in vivo study was carried out: materials were implanted, under general anesthesia, in critical size defects of rabbit femoral condyles; after 4 and 12 weeks, the healing rates and the quality of the regenerated bone were histomorphometrically calculated. The SL2-treated defects healed better at 12 weeks with a more similar microarchitecture of the newly formed bone to normal bone in comparison with other materials, as demonstrated by bone volume fraction and trabecular thickness values.

Fresh osteochondral allotransplants: Outcomes, failures and future developments.

Osteochondral allografts are used to treat many different conditions as acute traumatic large-sized lesions, degenerative osteoarthritis, osteochondritis dissecans, avascular necrosis or in case of failure of previous procedures particularly in young patients for whom primary prosthesis is not desirable. Fresh allografts present the advantage of having mature viable hyaline cartilage, not causing donor morbidity, allowing the restoration of even large defects in a single surgical session. Conversely, they could account for risks of disease transmission, immunologic reactions, and for limited availability. The present review aimed to analyze published studies of the last decade in which patients received fresh osteochondral allografts by dividing them for knee or ankle regenerative purposes. We wish to report the observed failure rates and particularly to collect any other reported side effect or outcome for identifying major problems and limits linked to the procedure and for delineating possible future researches and approaches. The overall success rates resulted ranging from 5.3% to 48.3% in the ankle at a mean follow up of 3.3 years and from 0% to 85.7% in the knee at a mean follow up of 7.1 years. Among other outcomes, occurrence or progression of arthritis, osteolysis, graft instability, fractures, nonunions, edema and infections were recorded. Overall, the lack of well designed randomized and controlled clinical trials, of immunological determination of the anti-donor antibodies development and of local and systemic biomarkers to detect reaction to the graft seems to be the major drawback. Improvements in these limiting factors might be desirable in order to enhance the clinical scenario of a well-established and successful procedure to give, especially for young patients, a real regeneration of the joint.