Effectiveness of a novel hydrolyzed collagen formulation in treating patients with symptomatic knee osteoarthritis: a multicentric retrospective clinical study.

PURPOSE: Knee osteoarthritis (OA) is a musculoskeletal disorder that may have a heavy impact on the patients' quality of life. Intra-articular collagen injection may be a safe adjuvant. Recently, CHondroGrid (CG), a hydrolyzed (< 3 kDa) bovine collagen injectable formulation, has been placed on the market. The aim of this study was to investigate the safety and performance profile of CG. METHODS: Patients affected by Kellgren Lawrence grade 1 to 4 knee OA and BMI < 30 were treated by administering three CG injections of 2 ml (4 mg) each (at 15 days and 45 days from the first one, respectively) and were followed up for six months after the last administration. Clinical records were retrospectively assessed to compare VAS, Lequesne and WOMAC total, pain, stiffness, and physical function scores collected at baseline and 15, 45, and 225 days after the first injection. RESULTS: At the last follow-up, 70 patients (37 men and 33 women, aged 57.1 ± 14.5 years) treated with CG showed a 50% reduction in their median Lequesne score, a 50% reduction in their VAS score at rest and moving, and a ≥ 50% reduction for all other scores under consideration. CONCLUSIONS: CG may be a safe and effective adjuvant in the treatment of symptomatic knee OA.

Real-time sonoelastography: principles and clinical applications in tendon disorders. A systematic review.

BACKGROUND: Sonoelastography (SE) is a new ultrasound-based method adopted in an increased number of scientific reports to analyse normal and pathological tendons. The aim of this study is to provide a systematic overview of clinical applications of SE in normal and pathological tendons. METHODS: A systematic research of PubMed, Ovid, and Cochrane Library electronic databases was performed according to PRISMA guideline. Two Authors searched and evaluated the articles independently; a third Author was involved to solve any disagreement. The Oxford Level of Evidence (LoE) was used to assess each article. RESULTS: There is an increasing interest in the application of SE in the evaluation of healthy and diseased tendons. Many different tendons are amenable for SE evaluation, such as the Achilles and patellar tendons, rotator cuff, common extensor tendons, quadriceps tendon, and the plantar fascia. CONCLUSION: SE appears to be a very useful diagnostic tool, in particular in tendon pathology. This is a dynamic examination, provides an immediate evaluation of the tissue elasticity, and may be useful in recognizing tendon abnormalities and in implementing the information available with conventional US. LEVEL OF EVIDENCE: IV.

Nutraceutical supplement in the management of tendinopathies: a systematic review.

BACKGROUND: nutraceuticals are common support therapy for management of tendinopathies. Even if they are widely diffused, our knowledge is still poor. The aim of this systematic review is to analyze the most commonly used nutraceuticals and their effects on tendons. METHODS: glucosamine and chondroitin sulphate, vitamin C, hydrolazed type 1 collagen, arginine alpha-keto-glutarate, bromelain, curcumin, boswellic acid, and methil-sulfonil-methane were considered. During the last week of Dicember 2015 a comprehensive research of main databases for each substance was made in relation with tendinopathy. Repeated articles, articles not in English nor in Italian, not common nutraceuticals, and articles not related with tendons or tenocytes were excluded. Clinical article quality was assessed independently by two reviewers using the modified Coleman methodology score. RESULTS: preclinical and clinical data from 46 articles from all databases were analyzed. All these nutraceuticals demonstrated several effects on normal and pathological tendons. Preclinical and clinical studies showed a possible role on collagen synthesis, inflammation, mechanical properties, and maturation of collagen bundles, antioxidant effect, edema, and analgesia. The majority clinical studies had some methodological limitations with an average Modified Coleman Methodology Score of 51.3 points and SD of 20.5 points. In particular, there were very low values in power, error, outcome assessment, and clinical effect. CONCLUSION: preclinical results are very encouraging, however they are not fully confirmed by clinical studies. There are few clinical papers on the use of nutraceuticals in tendon disorders, and their methodological quality is poor. Furthermore, in most of the studies more than one supplement was administered at the same time. This may bias the results, and the effect of each single component cannot be determined. Furthermore, the interactions between nutraceuticals and drugs, or other dietary supplements (especially at high doses) has not been evaluated, neither their effects on chronic diseases. For these reasons, it is not possible to draw any definitive raccomendations on the use of nutraceutical supplementation in tendinopathies.

Biological augmentation and tissue engineering approaches in meniscus surgery.

PURPOSE: The purpose of this review was to evaluate the role of biological augmentation and tissue engineering strategies in meniscus surgery. Although clinical (human), preclinical (animal), and in vitro tissue engineering studies are included here, we have placed additional focus on addressing preclinical and clinical studies reported during the 5-year period used in this review in a systematic fashion while also providing a summary review of some important in vitro tissue engineering findings in the field over the past decade. METHODS: A search was performed on PubMed for original works published from 2009 to March 31, 2014 using the term "meniscus" with all the following terms: "scaffolds," "constructs," "cells," "growth factors," "implant," "tissue engineering," and "regenerative medicine." Inclusion criteria were the following: English-language articles and original clinical, preclinical (in vivo), and in vitro studies of tissue engineering and regenerative medicine application in knee meniscus lesions published from 2009 to March 31, 2014. RESULTS: Three clinical studies and 18 preclinical studies were identified along with 68 tissue engineering in vitro studies. These reports show the increasing promise of biological augmentation and tissue engineering strategies in meniscus surgery. The role of stem cell and growth factor therapy appears to be particularly useful. A review of in vitro tissue engineering studies found a large number of scaffold types to be of promise for meniscus replacement. Limitations include a relatively low number of clinical or preclinical in vivo studies, in addition to the fact there is as yet no report in the literature of a tissue-engineered meniscus construct used clinically. Neither does the literature provide clarity on the optimal meniscus scaffold type or biological augmentation with which meniscus repair or replacement would be best addressed in the future. There is increasing focus on the role of mechanobiology and biomechanical and biochemical cues in this process, however, and it is hoped that this may lead to improvements in this strategy. CONCLUSIONS: There appears to be significant potential for biological augmentation and tissue engineering strategies in meniscus surgery to enhance options for repair and replacement. However, there are still relatively few clinical studies being reported in this regard. There is a strong need for improved translational activities and infrastructure to link the large amounts of in vitro and preclinical biological and tissue engineering data to clinical application. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies.

Oral chondroprotection with nutraceuticals made of chondroitin sulphate plus glucosamine sulphate in osteoarthritis.

Oral supplementation of chondroitin sulphate plus glucosamine helps repair the articular surface in osteoarthritis. Chondroitin-S reduces the concentration of the pro-inflammatory cytokines and transcription factor involved in inflammation. GlcN.S enhances cartilage specific matrix components and prevents collagen degeneration in chondrocytes by inhibiting hydrolytic enzymes, and preventing the oxidation of lipids and proteins. Chondroitin-S plus GlcN.S are slow-acting drugs that alleviate pain and partly restore joint function in OA patients. Orally administered pharmaceutical-grade chondroitin-S plus GlcN.S stabilize the joint space narrowing and significantly decrease the number of patients with new erosive OA. They are safe and no adverse events have ever been reported; they are recommended by EULAR and OARSI. The cost/effectiveness of the oral chondroitin-S plus GlcN.S therapy derives from the reduction of costs for physiotherapy, and for gastroprotective and non-steroidal drugs. The synergistic association of these two world-widely preferred nutraceuticals is a step forward in the management of OA.

Chitosan stabilizes platelet growth factors and modulates stem cell differentiation toward tissue regeneration.

The idea of using chitosan as a functional delivery aid to support simultaneously PRP, stem cells and growth factors (GF) is associated with the intention to use morphogenic biomaterials to modulate the natural healing sequence in bone and other tissues. For example, chitosan-chondroitin sulfate loaded with platelet lysate was included in a poly(D,L-lactate) foam that was then seeded with human adipose-derived stem cells and cultured in vitro under osteogenic stimulus: the platelet lysate provided to the bone tissue the most suitable assortment of GF which induces the osteogenic differentiation of the mesenchymal stem cells. PDGF, FGF, IGF and TGF-ß were protagonists in the repair of callus fractures. The release of GF from the composites of chitosan-PRP and either nano-hydroxyapatite or tricalcium phosphate was highly beneficial for enhancing MSC proliferation and differentiation, thus qualifying chitosan as an excellent vehicle. A number of biochemical characteristics of chitosan exert synergism with stem cells in the regeneration of soft tissues.

Late-diagnosed large osteochondral fracture of the lateral femoral condyle in an adolescent: a case report.

In this case report, we describe a large osteochondral fracture of the anterolateral femoral condyle in an adolescent athlete while dancing. At 3 months after the misdiagnosed injury, the condylar defect was covered by a layer of disorganized fibrous tissue rich in blood vessels. To achieve good repair, an accurate curettage of the fractured surfaces, a precise reduction, and a stable internal fixation of the fragments were performed. Two poly-L-lactic acid bioabsorbable screws were used to obtain appropriate compression. At the 2-year follow-up, the patient was asymptomatic and had resumed her previous dancing activity. An MRI scan showed no interruptions of the cartilage layer at the boundary with the healthy tissue, but cartilage thinning and extensive subchondral remodeling were detected.

Purified collagen I oriented membrane for tendon repair: an ex vivo morphological study.

Injured tendons have limited repair ability after full-thickness lesions. Tendon regeneration properties and adverse reactions were assessed ex vivo in an experimental animal model using a new collagen I membrane. The multilamellar membrane obtained from purified equine Achilles tendon is characterized by oriented collagen I fibers and has been shown to sustain cell growth and orientation in vitro. The central third of the patellar tendon (PT) of 10 New Zealand White rabbits was sectioned and grafted with the collagen membrane; the contralateral PT was cut longitudinally (sham-operated controls). Animals were euthanized 1 or 6 months after surgery, and tendons were subjected to histological and Synchrotron Radiation-based Computed Microtomography (SRµCT) examination and 3D structure analysis. Histological and SRµCT findings showed satisfactory graft integration with native tendon. Histological examination also showed ongoing angiogenesis. Adverse side-effects (inflammation, rejection, calcification) were not observed. The multilamellar collagen I membrane can be considered as an effective tool for tendon defect repair and tendon augmentation.

Matrix-induced autologous chondrocyte implantation (MACI) in the knee.

PURPOSE: Matrix-induced autologous chondrocyte implantation (MACI) has been in use for chondral defect repair since 2000, but to date, only little is known about its histological outcomes in the repair of knee cartilage defects. This prospective multicentre study aims to evaluate (1) the quality of the repair tissue obtained from biopsies taken during second-look arthroscopy and (2) the relationship between the histological outcome, the macroscopic appearance of the repair and the patients' functional status. METHODS: Thirty-three second-look core biopsies from 30 patients treated with MACI were analysed. At the time of biopsy, the surgeon reported the reason for the second-look arthroscopy, the quality of the repair tissue and the patient's functional status on a standardised form. Biopsies together with patient data were sent to our centre to undergo blind histological evaluation and data analysis. RESULTS: The median overall ICRS II histological score of the examined population was 57 (1st-3rd quartile 41-75). According to the ICRS cartilage repair assessment (CRA) arthroscopic evaluation, 10 biopsies (30%) were classified as normal, 17 (51%) as nearly normal, 4 (12%) as abnormal and 2 (6%) as severely abnormal. The histological outcome was not significantly related either to the macroscopic appearance of the lesion or to the patient's functional status at the time of biopsy. CONCLUSIONS: In the examined population, the macroscopic appearance of the repair tissue gave an overly favourable impression in comparison with the real histological composition of the tissue, which was possibly still maturing in many cases. The healing process after MACI needs to be better understood through a larger histological study, and a longer follow-up is needed to better clarify the relationship between histology and long-term functional status. LEVEL OF EVIDENCE: IV.

Chitosan, hyaluronan and chondroitin sulfate in tissue engineering for cartilage regeneration: a review.

Injection of hyaluronan into osteoarthritic joints restores the viscoelasticity, augments the flow of joint fluid, normalizes endogenous hyaluronan synthesis, and improves joint function. Chitosan easily forms polyelectrolyte complexes with hyaluronan and chondroitin sulfate. Synergy of chitosan with hyaluronan develops enhanced performances in regenerating hyaline cartilage, typical results being structural integrity of the hyaline-like neocartilage, and reconstitution of the subchondral bone, with positive cartilage staining for collagen-II and GAG in the treated sites. Chitosan qualifies for the preparation of scaffolds intended for the regeneration of cartilage: it yields mesoporous cryogels; it provides a friendly environment for chondrocytes to propagate, produce typical ECM, and assume the convenient phenotype; it is a good carrier for growth factors; it inactivates metalloproteinases thus preventing collagen degradation; it is suitable for the induction of the chondrogenic differentiation of mesenchymal stem cells; it is a potent means for hemostasis and platelet delivery.

Arthroscopic knee cartilage repair with covered microfracture and bone marrow concentrate.

In recent years several single-stage cartilage repair approaches have been devised to treat focal cartilage lesions. These usually associate microfracture (MFX) and a coverage scaffold. We describe a novel arthroscopic technique that combines MFX, autologous bone marrow concentrate (BMC), and a protective scaffold. Bone marrow aspirate from the iliac crest is centrifuged to obtain BMC. The cartilage defect is debrided, MFX holes are created, and the final defect is measured by use of a bent K-wire. The scaffold is then shaped to match the defect, immersed in BMC, introduced into the joint with a grasper, and fixed in place with a mixture of fibrin glue and BMC. This technique aims to augment the original single-stage procedure with a number of mesenchymal stem cells and growth factors contained in the BMC, to increase the defect filling and the rate of hyaline-like cartilage regeneration. The procedure combining MFX, BMC, and a protective scaffold is inexpensive and reproducible and has already shown the ability to regenerate hyaline-like cartilage. Its use as an alternative to autologous chondrocyte implantation requires further investigation.

Collagen I membranes for tendon repair: effect of collagen fiber orientation on cell behavior.

Tendons have poor spontaneous regenerative capabilities, and complete regeneration is never achieved despite intensive remodeling. In this in vitro study, we characterized two multilamellar collagen I membranes differing in the arrangement of collagen fiber deposition (oriented vs. nonoriented) and compared their mechanical properties. Human dermal fibroblasts and tenocytes were seeded on the two membranes to evaluate the effect of fiber orientation on cell viability and cytoskeletal organization. Results demonstrate that the multilamellar collagen I membrane with oriented fibers has the better mechanical properties and affords optimum cell proliferation and adhesion. Its fiber arrangement provides an instructive pattern for cell growth and may serve to guide the alignment of cells migrating from the ends of a crushed or frayed tendon to obtain a strong, correctly structured tendon, thus providing a viable clinical option for tendon repair.