Cell-based therapies have disease-modifying effects on osteoarthritis in animal models: A systematic review by the ESSKA Orthobiologic Initiative. Part 3: Umbilical cord, placenta, and other sources for cell-based injectable therapies.

PURPOSE: This systematic review aimed to investigate in animal models the presence of disease-modifying effects driven by non-bone marrow-derived and non-adipose-derived products, with a particular focus on umbilical cord and placenta-derived cell-based therapies for the intra-articular injective treatment of osteoarthritis (OA). METHODS: A systematic review was performed on three electronic databases (PubMed, Web of Science and Embase) according to PRISMA guidelines. The results were synthesised to investigate disease-modifying effects in preclinical animal studies comparing injectable umbilical cord, placenta, and other sources-derived products with OA controls. The risk of bias was assessed using the SYRCLE tool. RESULTS: A total of 80 studies were included (2314 animals). Cell therapies were most commonly obtained from the umbilical cord in 33 studies and placenta/amniotic tissue in 18. Cell products were xenogeneic in 61 studies and allogeneic in the remaining 19 studies. Overall, 25/27 (92.6%) of studies on umbilical cord-derived products documented better results compared to OA controls in at least one of the following outcomes: macroscopic, histological and/or immunohistochemical findings, with 19/22 of studies (83.4%) show positive results at the cartilage level and 4/6 of studies (66.7%) at the synovial level. Placenta-derived injectable products documented positive results in 13/16 (81.3%) of the studies, 12/15 (80.0%) at the cartilage level, and 2/4 (50.0%) at the synovial level, but 2/16 studies (12.5%) found overall worse results than OA controls. Other sources (embryonic, synovial, peripheral blood, dental pulp, cartilage, meniscus and muscle-derived products) were investigated in fewer preclinical studies. The risk of bias was low in 42% of items, unclear in 49%, and high in 9% of items. CONCLUSION: Interest in cell-based injectable therapies for OA treatment is soaring, particularly for alternatives to bone marrow and adipose tissue. While expanded umbilical cord mesenchymal stem cells reported auspicious disease-modifying effects in preventing OA progression in animal models, placenta/amniotic tissue also reported deleterious effects on OA joints. Lower evidence has been found for other cellular sources such as embryonic, synovial, peripheral blood, dental-pulp, cartilage, meniscus, and muscle-derived products. LEVEL OF EVIDENCE: Level II.

Human Osteoblasts' Response to Biomaterials for Subchondral Bone Regeneration in Standard and Aggressive Environments.

Osteochondral lesions, when not properly treated, may evolve into osteoarthritis (OA), especially in the elderly population, where altered joint function and quality are usual. To date, a collagen/collagen-magnesium-hydroxyapatite (Col/Col-Mg-HAp) scaffold (OC) has demonstrated good clinical results, although suboptimal subchondral bone regeneration still limits its efficacy. This study was aimed at evaluating the in vitro osteogenic potential of this scaffold, functionalized with two different strategies: the addition of Bone Morphogenetic Protein-2 (BMP-2) and the incorporation of strontium (Sr)-ion-enriched amorphous calcium phosphate (Sr-ACP) granules. Human osteoblasts were seeded on the functionalized scaffolds (OC+BMP-2 and OC+Sr-ACP, compared to OC) under stress conditions reproduced with the addition of H2O2 to the culture system, as well as in normal conditions, and evaluated in terms of morphology, metabolic activity, gene expression, and matrix synthesis. The OC+BMP-2 scaffold supported a better osteoblast morphology and stimulated scaffold colonization, cell activity, and extracellular matrix secretion, especially in the stressed culture environment but also in normal culture conditions, with increased expression of genes related to osteoblast differentiation. In conclusion, the incorporation of BMP-2 into the Col/Col-Mg-HAp scaffold also represents an improvement of the osteochondral scaffold in more challenging conditions, supporting further preclinical studies to optimize it for use in clinical practice.

A Comparison Between Polyurethane and Collagen Meniscal Scaffold for Partial Meniscal Defects: Similar Positive Clinical Results at a Mean of 10 Years of Follow-Up.

PURPOSE: To compare, at long-term follow-up, the clinical outcomes and failures of collagen and polyurethane meniscal scaffolds for the treatment of partial meniscal defects. METHODS: Patients affected by partial meniscal defect with intact anterior and posterior meniscal attachments and an intact rim at the circumference of the missing meniscus were included, treated with a collagen meniscal implant or with polyurethane scaffold, and clinically evaluated by analysis of the subjective International Knee Documentation Committee score, the visual analog scale score for the evaluation of knee function and symptoms, and the Tegner score to assess the activity level. RESULTS: After 3 patients dropped out, a total of 47 patients, comprising 31 men and 16 women, with a mean age of 43 ± 14.1 years and mean body mass index of 25 ± 1.4, were clinically evaluated up to a mean of 10 years' follow-up. The International Knee Documentation Committee score improved from 42.9 ± 15.9 to 67.4 ± 12.4 (P < .0005) in the polyurethane implant group and from 46.8 ± 16.7 to 62.1 ± 22.6 (P < .0005) in the collagen meniscal implant group. The visual analog scale score decreased significantly from baseline values of 5.4 ± 2.3 and 4.4 ± 1.7, to 3.4 ± 2.5 and 2.7 ± 2.4, respectively, at final follow-up in the polyurethane implant (P = .002) and collagen meniscal implant (P < .0005) groups. The Tegner score improved in both groups without reaching the preinjury activity level. No significant differences in the scores were found between the polyurethane and collagen scaffold groups. A total of 10 implants failed, 5 per group, for a cumulative failure rate of 21.3%, with no differences between the 2 scaffolds. CONCLUSIONS: The long-term comparison showed positive and similar results for both polyurethane- and collagen-based meniscal scaffolds, with an implant survival rate of about 80% at 10 years of follow-up and no differences in terms of pain, function, and activity level. LEVEL OF EVIDENCE: Level IV, case-control comparative study.

Polyurethane scaffold implants for partial meniscus lesions: delayed intervention leads to an inferior outcome.

PURPOSE: The purpose of this study was to assess the clinical outcomes of the implantation of an aliphatic polyurethane scaffold for the treatment of partial loss of meniscal tissue at a mean follow-up of 36 months. METHODS: A retrospective review on prospectively collected data was performed on patients who underwent implantation of an aliphatic polyurethane-based synthetic meniscal scaffold. Patients were evaluated for demographics data, lesion and implant characteristics (sizing, type and number of meniscal sutures), previous and combined surgeries and complications. Clinical parameters were rated using NRS, IKDC subjective, Lysholm, KOOS, and Tegner activity score, both preoperatively and at final follow-up. RESULTS: Sixty-seven patients were evaluated at a mean follow-up of 36 months (48 M and 19 F; mean age 40.8 ± 10.6 years; mean BMI 25.4 ± 4.3). The scaffold was implanted on the medial side in 54 cases, and on the lateral one in 13. Forty-seven patients had undergone previous surgical treatment at the same knee and 45 required combined surgical procedures. All evaluated scores improved significantly from the baseline. Among possible prognostic factors, a delayed scaffold implantation had lower post-operative clinical scores: IKDC subjective (P = 0.049), KOOS Sport (P = 0.044), KOOS total (p = 0.011), and Tegner (P = 0.03) scores at follow-up. CONCLUSIONS: The polyurethane meniscal scaffold implantation led to a significant clinical benefit in a large number of patients. A delayed intervention correlated with worse results. LEVEL OF EVIDENCE: IV.

Novel alginate biphasic scaffold for osteochondral regeneration: an in vivo evaluation in rabbit and sheep models.

Current therapeutic strategies for osteochondral restoration showed a limited regenerative potential. In fact, to promote the growth of articular cartilage and subchondral bone is a real challenge, due to the different functional and anatomical properties. To this purpose, alginate is a promising biomaterial for a scaffold-based approach, claiming optimal biocompatibility and good chondrogenic potential. A previously developed mineralized alginate scaffold was investigated in terms of the ability to support osteochondral regeneration both in a large and medium size animal model. The results were evaluated macroscopically and by microtomography, histology, histomorphometry, and immunohistochemical analysis. No evidence of adverse or inflammatory reactions was observed in both models, but limited subchondral bone formation was present, together with a slow scaffold resorption time.The implantation of this biphasic alginate scaffold provided partial osteochondral regeneration in the animal model. Further studies are needed to evaluate possible improvement in terms of osteochondral tissue regeneration for this biomaterial.

A multilayer biomaterial for osteochondral regeneration shows superiority vs microfractures for the treatment of osteochondral lesions in a multicentre randomized trial at 2 years.

PURPOSE: The increasing awareness on the role of subchondral bone in the etiopathology of articular surface lesions led to the development of osteochondral scaffolds. While safety and promising results have been suggested, there are no trials proving the real potential of the osteochondral regenerative approach. Aim was to assess the benefit provided by a nanostructured collagen-hydroxyapatite (coll-HA) multilayer scaffold for the treatment of chondral and osteochondral knee lesions. METHODS: In this multicentre randomized controlled clinical trial, 100 patients affected by symptomatic chondral and osteochondral lesions were treated and evaluated for up to 2 years (51 study group and 49 control group). A biomimetic coll-HA scaffold was studied, and bone marrow stimulation (BMS) was used as reference intervention. Primary efficacy measurement was IKDC subjective score at 2 years. Secondary efficacy measurements were: KOOS, IKDC Knee Examination Form, Tegner and VAS Pain scores evaluated at 6, 12 and 24 months. Tissue regeneration was evaluated with MRI MOCART scoring system at 6, 12 and 24 months. An external independent agency was involved to ensure data correctness and objectiveness. RESULTS: A statistically significant improvement of all clinical scores was obtained from basal evaluation to 2-year follow-up in both groups, although no overall statistically significant differences were detected between the two treatments. Conversely, the subgroup of patients affected by deep osteochondral lesions (i.e. Outerbridge grade IV and OCD) showed a statistically significant better IKDC subjective outcome (+12.4 points, p = 0.036) in the coll-HA group. Statistically significant better results were also found for another challenging group: sport active patients (+16.0, p = 0.027). Severe adverse events related to treatment were documented only in three patients in the coll-HA group and in one in the BMS group. The MOCART score showed no statistical difference between the two groups. CONCLUSIONS: This study highlighted the safety and potential of a biomimetic implant. While no statistically significant differences were found compared to BMS for chondral lesions, this procedure can be considered a suitable option for the treatment of osteochondral lesions. LEVEL OF EVIDENCE: I.

Injectable Systems for Intra-Articular Delivery of Mesenchymal Stromal Cells for Cartilage Treatment: A Systematic Review of Preclinical and Clinical Evidence.

Stem cell-based therapy is a promising approach to treat cartilage lesions and clinical benefits have been reported in a number of studies. However, the efficacy of cell injection procedures may be impaired by cell manipulation and damage as well as by cell dissemination to non-target tissues. To overcome such issues, mesenchymal stromal cell (MSC) delivery may be performed using injectable vehicles as containment systems that further provide a favorable cell microenvironment. The aim of this systematic review was to analyze the preclinical and clinical literature on platelet-rich plasma (PRP), hyaluronic acid (HA), and hydrogels for the delivery of MSCs. The systematic literature search was performed using the PubMed and Web of science databases with the following string: "(stem cells injection) AND (platelet rich plasma OR PRP OR platelet concentrate OR biomaterials OR hyaluronic acid OR hydrogels)": 40 studies (19 preclinical and 21 clinical) met the inclusion criteria. This review revealed an increasing interest on the use of injectable agents for MSC delivery. However, while negligible adverse events and promising clinical outcomes were generally reported, the prevalence of low quality studies hinders the possibility to demonstrate the real benefits of using such injectable systems. Specific studies must be designed to clearly demonstrate the added benefits of these systems to deliver MSCs for the treatment of cartilage lesions and osteoarthritis.

Biodegradable polyurethane meniscal scaffold for isolated partial lesions or as combined procedure for knees with multiple comorbidities: clinical results at 2 years.

PURPOSE: The aim of this study is to evaluate the safety and clinical efficacy of this novel polyurethane meniscal scaffold to treat partial meniscal loss. METHODS: Eighteen patients (11 men and 7 women, mean age: 45 years) affected by irreparable acute meniscal tears requiring partial meniscectomy or chronic prior loss of meniscal tissue were enrolled in the study. They underwent arthroscopic polyurethane meniscal scaffold implantation (13 medial and 5 lateral) and, in case of presence of other comorbidities, concurrent procedures were also performed. Patients were prospectively evaluated up to 2 years of follow-up through IKDC objective, IKDC subjective, and Tegner scores. Furthermore, MRI evaluation of the meniscal scaffold was performed. RESULTS: No major adverse events were observed. A statistically significant increase in all the clinical parameters considered was found. The IKDC objective score increased from 61 % of normal or nearly normal knees at basal evaluation to 94 % at 2 years of follow-up (p = 0.01). There was also a significant increase in the IKDC subjective score both at 6-12 months of follow-up (p = 0.03 and p < 0.005), which was confirmed at 24 months. The Tegner score also showed a significant increase from the pre-operative level (median value 2, range 1-5) to final evaluation (median value 3, range 2-5; p = 0.005), albeit not reaching the pre-injury sports activity level. CONCLUSIONS: The implantation of this novel polyurethane scaffold proved to be a safe and potentially effective procedure to treat partial meniscal loss with encouraging results at short-term follow-up. Further high-quality studies with larger numbers of patients and longer evaluation times are needed to confirm these preliminary data.

Scaffold-based repair for cartilage healing: a systematic review and technical note.

PURPOSE: The aim of this systematic review was to address the treatment of chondral and osteochondral knee lesions through the use of scaffolds, by showing surgical options and results of this scaffold-based repair approach for the healing of the articular surface. METHODS: All studies published in English addressing cartilage scaffold-based treatment were identified, including those that fulfilled the following criteria: (1) Levels I to IV evidence addressing the outlined areas of interest, (2) measures of functional or clinical outcome, (3) knee cartilage lesions, and (4) minimum of 2 years of follow-up. RESULTS: The analysis showed a progressively increasing number of articles per year from 1995 to February 2012. The number of selected articles was 51, with 40 focusing on 2-step procedures and 11 focusing on 1-step procedures. The evaluation of evidence level showed 3 randomized studies, 10 comparative studies, 33 case series, and 5 case reports. CONCLUSIONS: Regenerative scaffold-based procedures are emerging as a therapeutic option for the treatment of chondral lesions, but well-designed studies are lacking. Systematic long-term evaluation of these techniques and randomized studies are necessary to confirm the potential of this treatment approach, especially compared with the available traditional treatments. Different 1-step scaffold-based strategies are emerging to simplify the procedure and reduce costs. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies.

ACI and MACI.

Regenerative procedures aim to recreate a hyaline-like tissue, thus restoring a biologically and biomechanically valid articular surface with durable clinical results. Autologous chondrocyte implantation (ACI) has been developed two decades ago, and both the production of a hyaline-like articular surface and a satisfactory clinical outcome have been documented at medium-long follow-up. Bioengineering technology further improved this regenerative treatment approach to include matrix-assisted ACI (MACI) techniques. These procedures have been introduced in the clinical practice one decade ago, showing similar results while at the same time overcoming most of the concerns related to the first-generation ACI. The use of scaffolds to create a cartilage-like tissue in a three-dimensional culture system allows for the optimization of the procedure from both the biological and surgical point of view. However, despite thousands of treated patients and many published studies suggesting good clinical results and durability of these procedures, the properties of healthy, normal articular cartilage are still unmatched by any available substitute. Both indications and results of these substitutes are still controversial. The role of many variables that may influence the final outcome still need to be clarified to further improve the potential benefits of these biological regenerative procedures.

Polyurethane Meniscal Scaffold for the Treatment of Partial Meniscal Deficiency: 5-Year Follow-up Outcomes: A European Multicentric Study.

BACKGROUND: A biodegradable polyurethane scaffold was developed to treat patients with the challenging clinical condition of painful partial meniscal defects. HYPOTHESIS: The use of an acellular polyurethane scaffold in patients with symptomatic partial meniscal defects would result in both midterm pain relief and improved function. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 155 patients with symptomatic partial meniscal defects (101 medial and 54 lateral) were implanted with a polyurethane scaffold in a prospective, single-arm, multicentric study with a minimum 5-year follow-up. Clinical outcomes were measured with the visual analog scale for pain, International Knee Documentation Committee subjective knee evaluation form, Lysholm knee scale, and Knee injury and Osteoarthritis Outcome Score at baseline and at 2- and 5-year follow-ups. Magnetic resonance imaging (MRI) was used to evaluate the knee joint, meniscal implant, and meniscal extrusion. Kaplan-Meier survival analysis was also performed. Removal of the scaffold, conversion to a meniscal transplant, and unicompartmental/total knee arthroplasty were used as endpoints. RESULTS: Eighteen patients were lost to follow-up (11.6%). The patients who were included in this study showed significant clinical improvement after surgery as indicated by the different outcome measures (P = .01). However, the clinical improvement tended to stabilize between 2 and 5 years of follow-up. MRI scans of the scaffolds in 56 patients showed a smaller-sized implant in the majority of the cases when compared with the native meniscus with an irregular surface at the 5-year follow-up. During the follow-up period, 87.6% of the implants survived in this study. At 5 years of follow-up, 87.9% of the medial scaffolds were still functioning versus 86.9% of the lateral scaffolds. In total, 23 treatments had failed: 10 removed scaffolds because of breakage, 7 conversions to meniscal allograft transplantation, 4 conversions to unicompartmental knee arthroplasty, and 2 conversions to total knee arthroplasty. CONCLUSION: The polyurethane meniscal implant was able to improve knee joint function and reduce pain in patients with segmental meniscal deficiency over 5 years after implantation. The MRI appearance of this scaffold was different from the original meniscal tissue at the midterm follow-up. The treatment survival rates of 87.9% of the medial scaffolds and 86.9% of the lateral scaffolds in the present study compared favorably with those published concerning meniscal allograft transplantation after total meniscectomy.

Vegetable hierarchical structures as template for bone regeneration: New bio-ceramization process for the development of a bone scaffold applied to an experimental sheep model.

Long bone defects still represent a major clinical challenge in orthopedics, with the inherent loss of function considerably impairing the quality of life of the affected patients. Thus, the purpose of this study was to assess the safety and potential of bone regeneration offered by a load-bearing scaffold characterized by unique hierarchical architecture and high strength, with active surface facilitating new bone penetration and osseointegration in critical size bone defects. The results of this study showed the potential of bio-ceramization processes applied to vegetable hierarchical structures for the production of new wood-derived bone scaffolds, further improved by surface functionalization, with good biological and mechanical properties leading to successful treatment of critical size bone defects in the sheep model. Future studies are needed to evaluate if these scaffolds prototypes, as either biomaterial alone or in combination with augmentation strategies, may represent an optimal solution to enhance bone regeneration in humans.

The Role of Three-Dimensional Scaffolds in Treating Long Bone Defects: Evidence from Preclinical and Clinical Literature-A Systematic Review.

Long bone defects represent a clinical challenge. Bone tissue engineering (BTE) has been developed to overcome problems associated with conventional methods. The aim of this study was to assess the BTE strategies available in preclinical and clinical settings and the current evidence supporting this approach. A systematic literature screening was performed on PubMed database, searching for both preclinical (only on large animals) and clinical studies. The following string was used: "(Scaffold OR Implant) AND (Long bone defect OR segmental bone defect OR large bone defect OR bone loss defect)." The search retrieved a total of 1573 articles: 51 preclinical and 4 clinical studies were included. The great amount of preclinical papers published over the past few years showed promising findings in terms of radiological and histological evidence. Unfortunately, this in vivo situation is not reflected by a corresponding clinical impact, with few published papers, highly heterogeneous and with small patient populations. Several aspects should be further investigated to translate positive preclinical findings into clinical protocols: the identification of the best biomaterial, with both biological and biomechanical suitable properties, and the selection of the best choice between cells, GFs, or their combination through standardized models to be validated by randomized trials.

European definitions, current use, and EMA stance of platelet-rich plasma in sports medicine.

Platelet-rich plasma has been the focus of much attention over the last few years as an appealing biological approach to favor the healing of tissues otherwise doomed by a low healing potential. In Europe, the regulatory framework concerning the blood system is currently disciplined by Directive 2002/98/EC of the European Parliament and Council of January 27, 2003, which sets out quality and safety rules for collecting, controlling, processing, preserving, and distributing human blood and its components, acknowledged in the various States of the Union with internal regulations. This lack of homogeneity in the European legal landscape will probably lead the Community legislature to intervene in the near future, to even out the "rules of engagement" of this peculiar class of biomaterials.

Clinical results and MRI evolution of a nano-composite multilayered biomaterial for osteochondral regeneration at 5 years.

BACKGROUND: Several cartilage lesions involve the subchondral bone, and there is a need for biphasic scaffolds to treat the entire osteochondral unit to reproduce the different biological and functional requirements and guide the growth of the 2 tissues. PURPOSE: To evaluate the results of a cell-free collagen-hydroxyapatite osteochondral scaffold at midterm, and to use magnetic resonance imaging (MRI) analysis to document the imaging evolution of the tissue regeneration process through 5 years of follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-seven patients (9 women, 18 men; mean age, 34.9 ± 10.2 years) treated for knee chondral or osteochondral lesions (size, 1.5-6 cm(2)) were followed for 2 and 5 years and were clinically evaluated using the International Knee Documentation Committee (IKDC) and Tegner scores. An MRI evaluation was performed at both follow-ups in 23 lesions, and the magnetic resonance observation of cartilage repair tissue (MOCART) score and specific subchondral bone parameters (bone regeneration, bone signal quality, osteophytes or upcoming bone front, sclerotic areas, and edema) were analyzed. RESULTS: A statistically significant improvement in all clinical scores was observed from the initial evaluation to the 2- and 5-year follow-ups, and the results were stable over time. The mean IKDC subjective score improved from 40.0 ± 15.0 to 76.5 ± 14.5 (2-year follow-up) and 77.1 ± 18.0 (5-year follow-up) and the mean Tegner score from 1.6 ± 1.1 to 4.0 ± 1.8 (2-year follow-up) and 4.1 ± 1.9 (5-year follow-up). The MRI evaluation showed a significant improvement in both the MOCART score and subchondral bone status from 2 to 5 years. At 5 years, complete filling of the cartilage was shown in 78.3% of the lesions, complete integration of the graft was detected in 69.6% of cases, the repair tissue surface was intact in 60.9%, and the structure of the repair tissue was homogeneous in 60.9% of the cases. No correlation was found between MRI findings and clinical outcome. CONCLUSION: This osteochondral scaffold was used for the treatment of chondral and osteochondral knee defects with a single-step procedure. The study results highlighted the safety and potential of this procedure, which offered a good clinical outcome with stable results at midterm follow-up. Although the MRI findings improved over time, some abnormalities persisted, but no correlation was found between the imaging and clinical results.

New bio-ceramization processes applied to vegetable hierarchical structures for bone regeneration: an experimental model in sheep.

Bone loss is still a major problem in orthopedics. The purpose of this experimental study is to evaluate the safety and regenerative potential of a new scaffold based on a bio-ceramization process for bone regeneration in long diaphyseal defects in a sheep model. The scaffold was obtained by transformation of wood pieces into porous biomorphic silicon carbide (BioSiC®). The process enabled the maintenance of the original wood microstructure, thus exhibiting hierarchically organized porosity and high mechanical strength. To improve cell adhesion and osseointegration, the external surface of the hollow cylinder was made more bioactive by electrodeposition of a uniform layer of collagen fibers that were mineralized with biomimetic hydroxyapatite, whereas the internal part was filled with a bio-hybrid HA/collagen composite. The final scaffold was then implanted in the metatarsus of 15 crossbred (Merinos-Sarda) adult sheep, divided into 3 groups: scaffold alone, scaffold with platelet-rich plasma (PRP) augmentation, and scaffold with bone marrow stromal cells (BMSCs) added during implantation. Radiological analysis was performed at 4, 8, 12 weeks, and 4 months, when animals were sacrificed for the final radiological, histological, and histomorphometric evaluation. In all tested treatments, these analyses highlighted the presence of newly formed bone at the bone scaffolds' interface. Although a lack of substantial effect of PRP was demonstrated, the scaffold+BMSC augmentation showed the highest value of bone-to-implant contact and new bone growth inside the scaffold. The findings of this study suggest the potential of bio-ceramization processes applied to vegetable hierarchical structures for the production of wood-derived bone scaffolds, and document a suitable augmentation procedure in enhancing bone regeneration, particularly when combined with BMSCs.

Orderly osteochondral regeneration in a sheep model using a novel nano-composite multilayered biomaterial.

The objective of this article was to investigate the safety and regenerative potential of a newly developed biomimetic scaffold when applied to osteochondral defects in an animal model. A new multilayer gradient nano-composite scaffold was obtained by nucleating collagen fibrils with hydroxyapatite nanoparticles. In the femoral condyles of 12 sheep, 24 osteochondral lesions were created. Animals were randomized into three treatment groups: scaffold alone, scaffold colonized in vitro with autologous chondrocytes and empty defects. Six months after surgery, the animals were sacrificed and the lesions were histologically evaluated. Histologic and gross evaluation of specimens showed good integration of the chondral surface in all groups except for the control group. Significantly better bone regeneration was observed both in the group receiving the scaffold alone and in the group with scaffold loaded with autologous chondrocytes. No difference in cartilage surface reconstruction and osteochondral defect filling was noted between cell-seeded and cell-free groups. In the control group, no bone or cartilage defect healing occurred, and the defects were filled with fibrous tissue. Quantitative macroscopic and histological score evaluations confirmed the qualitative trends observed. The results of the present study showed that this novel osteochondral scaffold is safe and easy to use, and may represent a suitable matrix to direct and coordinate the process of bone and hyaline-like cartilage regeneration. The comparable regeneration process observed with or without autologous chondrocytes suggests that the main mode of action of the scaffold is based on the recruitment of local cells.

A one-pot method to enhance dissolution rate of low solubility drug molecules using dispersion polymerization in supercritical carbon dioxide.

The surfactant assisted polymerization of 1-vinyl-2-pyrrolidone in supercritical carbon dioxide in the presence of Piroxicam, selected as a model of a low aqueous solubility drug, was studied in order to prepare in a single step a polymeric composite to enhance the rate of dissolution of the pharmaceutical compound. Reactive entrapping was carried out at 65 degrees C in the P range 21-38MPa. Under proper operative conditions we obtained the composite under the form of sub-micron spherical particles with relatively narrow particle size distribution. Drug loadings higher than 12% (w/w) were obtained and XRD and Raman spectroscopy suggest that the anti-inflammatory agent is dispersed in the matrix with a non-crystalline structure. The dissolution rate of the drug from the composites was significantly faster both than that of the pure compound and of its physical mixture with the polymer. Collected results suggest that the proposed one-pot process can be used to prepare polymer based composites to increase bioavailability of low solubility drugs without utilization of toxic solvents and under mild temperature conditions.

Second generation issues in cartilage repair.

In recent years, regenerative techniques, such as autologous chondrocyte implantation (ACI), have emerged as a potential therapeutic option for the treatment of chondral lesions. However, the good results reported have to be weighed against the number of problems that can be observed with traditional ACI methods. To address these problems, the so-called second generation ACI techniques have been developed. Autologous chondrocyte transplantation on a 3-dimensional matrix was introduced in clinical practice from 1998 to 1999 and results at short to medium-term follow-up are well documented for different types of scaffolds. These techniques may be used for the treatment of large chondral lesions in the young, active population and highly competitive athletes, but long-term and randomized controlled studies will be needed to confirm reliability of these procedures.