Alice Roffi

Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics

PurposeThe aim of this systematic review is to examine the available clinical evidence in the literature to support mesenchymal stem cell (MSC) treatment strategies in orthopaedics for cartilage defect regeneration.MethodsThe research was performed on the PubMed database considering the English literature from 2002 and using the following key words: cartilage, cartilage repair, mesenchymal stem cells, MSCs, bone marrow concentrate (BMC), bone marrow-derived mesenchymal stem cells, bone marrow stromal cells, adipose-derived mesenchymal stem cells, and synovial-derived mesenchymal stem cells.ResultsThe systematic research showed an increasing number of published studies on this topic over time and identified 72 preclinical papers and 18 clinical trials. Among the 18 clinical trials identified focusing on cartilage regeneration, none were randomized, five were comparative, six were case series, and seven were case reports; two concerned the use of adipose-derived MSCs, five the use of BMC, and 11 the use of bone marrow-derived MSCs, with preliminary interesting findings ranging from focal chondral defects to articular osteoarthritis degeneration.ConclusionsDespite the growing interest in this biological approach for cartilage regeneration, knowledge on this topic is still preliminary, as shown by the prevalence of preclinical studies and the presence of low-quality clinical studies. Many aspects have to be optimized, and randomized controlled trials are needed to support the potential of this biological treatment for cartilage repair and to evaluate advantages and disadvantages with respect to the available treatments.Level of evidenceIV.

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.

Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration

PurposeThe aim of this review was to analyze the available evidence on the clinical application of this biological approach for the injective treatment of cartilage lesions and joint degeneration, together with preclinical studies to support the rationale for the use of platelet concentrates, to shed some light and give indications on what to treat and what to expect from intra-articular injections of platelet-rich plasma (PRP).MethodsAll in vitro, in vivo preclinical and clinical studies on PRP injective treatment in the English language concerning the effect of PRP on cartilage, synovial tissue, menisci, and mesenchymal stem cells were considered. A systematic review on the PubMed database was performed using the following words: (platelet-rich plasma or PRP or platelet concentrate or platelet lysate or platelet supernatant) and (cartilage or chondrocytes or synoviocytes or menisci or mesenchymal stem cells).ResultsFifty-nine articles met the inclusion criteria: 26 were in vitro, 9 were in vivo, 2 were both in vivo and in vitro, and 22 were clinical studies. The analysis showed an increasing number of published studies over time. Preclinical evidence supports the use of PRP injections that might promote a favourable environment for joint tissues healing. Only a few high-quality clinical trials have been published, which showed a clinical improvement limited over time and mainly documented in younger patients not affected by advanced knee degeneration.ConclusionsBesides the limits and sometimes controversial findings, the preclinical literature shows an overall support toward this PRP application. An intra-articular injection does not just target cartilage; instead, PRP might influence the entire joint environment, leading to a short-term clinical improvement. Many biological variables might influence the clinical outcome and have to be studied to optimize PRP injective treatment of cartilage degeneration and osteoarthritis.Level of evidenceIV.

New trends for knee cartilage regeneration: from cell-free scaffolds to mesenchymal stem cells

In the last decade, huge steps forward have been made in the field of cartilage regeneration. The most recent trend for treating chondral/osteochondral lesions is based on the application of smart biomaterials that could lead to “in situ” regeneration of not only cartilage, but also subchondral bone, preferably through a single step procedure to reduce the costs and the morbidity for the patient. This innovative approach is currently under investigation as several “scaffolds” have been proposed in clinical practice, with or without the aid of cells, with the opportunity, in the second case, of bypassing the strict limits imposed by cell manipulation regulations. Furthermore, the fascinating potential of mesenchymal stem cells has recently opened new paths of research to discover how and whether these powerful entities can really contribute to tissue regeneration. The first clinical trials have been published but further high quality research is needed to understand their mechanisms of action, their limits, and their clinical efficacy.

Stem cells in articular cartilage regeneration

BackgroundMesenchymal stem cells (MSCs) have emerged as a promising option to treat articular chondral defects and early OA stages. However, their potential and limitations for clinical use remain controversial. Thus, the aim of this systematic review was to examine MSCs treatment strategies in order to summarize the current clinical evidence for the treatment of cartilage lesions and OA. MethodsA systematic review of the literature was performed on the PubMed database using the following string: “cartilage treatment” AND “mesenchymal stem cells”. The filters included publications on the clinical use of MSCs for cartilage defects and OA in English language up to 2015. ResultsOur search identified 1639 papers: 60 were included in the analysis, with an increasing number of studies published on this topic over time. Seven were randomized, 13 comparative, 31 case series, and 9 case reports; 26 studies reported the results after injective administration, whereas 33 used surgical implantation. One study compared the 2 different modalities. With regard to the cell source, 20 studies concerned BMSCs, 17 ADSCs, 16 BMC, 5 PBSCs, 1 SDSCs, and 1 compared BMC vs PBSCs. ConclusionsThe available studies allow to draw some indications. First, no major adverse events related to the treatment or to the cell harvest have been reported. Second, a clinical benefit of using MSCs therapies has been reported in most of the studies, regardless of cell-source, indication or administration method. Third, young age, lower BMI, smaller lesion size for focal lesions and earlier stages of OA joints, have been shown to correlate with better outcomes, even though the available data strength doesn’t allow to define clear cutoff values.

Adipose-Derived Mesenchymal Stem Cells for the Treatment of Articular Cartilage: A Systematic Review on Preclinical and Clinical Evidence

Among the current therapeutic approaches for the regeneration of damaged articular cartilage, none has yet proven to offer results comparable to those of native hyaline cartilage. Recently, it has been claimed that the use of mesenchymal stem cells (MSCs) provides greater regenerative potential than differentiated cells, such as chondrocytes. Among the different kinds of MSCs available, adipose-derived mesenchymal stem cells (ADSCs) are emerging due to their abundancy and easiness to harvest. However, their mechanism of action and potential for cartilage regeneration are still under investigation, and many other aspects still need to be clarified. The aim of this systematic review is to give an overview of in vivo studies dealing with ADSCs, by summarizing the main evidence for the treatment of cartilage disease of the knee.

Does Platelet-Rich Plasma Freeze-Thawing Influence Growth Factor Release and Their Effects on Chondrocytes and Synoviocytes?

PRP cryopreservation remains a controversial point. Our purpose was to investigate the effect of freezing/thawing on PRP molecule release, and its effects on the metabolism of chondrocytes and synoviocytes. PRP was prepared from 10 volunteers, and a half volume underwent one freezing/thawing cycle. IL-1β, HGF, PDGF AB/BB, TGF-β1, and VEGF were assayed 1 hour and 7 days after activation. Culture media of chondrocytes and synoviocytes were supplemented with fresh or frozen PRP, and, at 7 days, proliferation, gene expression, and secreted proteins levels were evaluated. Results showed that in the freeze-thawed PRP the immediate and delayed molecule releases were similar or slightly lower than those in fresh PRP. TGF-β1 and PDGF AB/BB concentrations were significantly reduced after freezing both at 1 hour and at 7 days, whereas HGF concentration was significantly lower in frozen PRP at 7 days. In fresh PRP IL-1β and HGF concentrations underwent a significant further increase after 7 days. Similar gene expression was found in chondrocytes cultured with both PRPs, whereas in synoviocytes HGF gene expression was higher in frozen PRP. PRP cryopreservation is a safe procedure, which sufficiently preserves PRP quality and its ability to induce proliferation and the production of ECM components in chondrocytes and synoviocytes.

Platelet-Rich Plasma: The Choice of Activation Method Affects the Release of Bioactive Molecules

Platelet-Rich Plasma (PRP) is a low-cost procedure to deliver high concentrations of autologous growth factors (GFs). Platelet activation is a crucial step that might influence the availability of bioactive molecules and therefore tissue healing. Activation of PRP from ten voluntary healthy males was performed by adding 10% of CaCl2, 10% of autologous thrombin, 10% of a mixture of CaCl2 + thrombin, and 10% of collagen type I. Blood derivatives were incubated for 15 and 30 minutes and 1, 2, and 24 hours and samples were evaluated for the release of VEGF, TGF-β1, PDGF-AB, IL-1β, and TNF-α. PRP activated with CaCl2, thrombin, and CaCl2/thrombin formed clots detected from the 15-minute evaluation, whereas in collagen-type-I-activated samples no clot formation was noticed. Collagen type I produced an overall lower GF release. Thrombin, CaCl2/thrombin, and collagen type I activated PRPs showed an immediate release of PDGF and TGF-β 1 that remained stable over time, whereas VEGF showed an increasing trend from 15 minutes up to 24 hours. CaCl2 induced a progressive release of GFs from 15 minutes and increasing up to 24 hours. The method chosen to activate PRP influences both its physical form and the releasate in terms of GF amount and release kinetic.

Scaffolds for cartilage repair of the ankle joint: The impact on surgical practice

BACKGROUND Ideal management of osteochondral lesions in the ankle joint is still theme of debate. Scaffold-based repair is emerging as a new approach for regenerative treatment. METHODS Articles published in PubMed from 2000 to January 2012 addressing cartilage scaffold-based treatment were identified, including levels I-IV evidence clinical trials with measures of functional, clinical or imaging outcome. RESULTS The analysis showed a progressively increasing number of articles from 2000. The number of selected papers was 19:15 focusing on two-step and 4 on one-step procedures; no randomized studies, 3 comparative studies, 11 case series and 5 case reports were identified. CONCLUSIONS Regenerative surgical approach with scaffold-based procedures is emerging as a potential therapeutic option for the treatment of chondral lesions of the ankle. One step treatments simplify the procedure and the results reported are very close to the previous techniques. However, well-designed studies are lacking, and randomized long-term trials are necessary to confirm the potential of these techniques. LEVEL OF EVIDENCE Review - IV.

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.