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Platelet-derived growth factor-coated decellularized meniscus scaffold for integrative healing of meniscus tears.

ABSTRACT: The aim of this study was to examine the potential of platelet-derived growth factor (PDGF)-coated decellularized meniscus scaffold in mediating integrative healing of meniscus tears by inducing endogenous cell migration. Fresh bovine meniscus was chemically decellularized and covalently conjugated with heparin and PDGF-BB. In vitro PDGF release kinetics was measured. The scaffold was transplanted into experimental tears in avascular bovine meniscus explants and cultured for 2 and 4?weeks. The number migrating and proliferating cells at the borderline between the scaffold and injured explant and PDGF receptor-? (PDGFR?) expressing cells were counted. The alignment of the newly produced ECM and collagen was analyzed by Safranin-O, picrosirius red staining, and differential interference contrast (DIC). Tensile testing of the explants was performed after culture for 2 and 4?weeks. Heparin conjugated scaffold showed immobilization of high levels of PDGF-BB, with sustained release over 2?weeks. Insertion of the PDGF-BB treated scaffold in defects in avascular meniscus led to increased PDGFR? expression, cell migration and proliferation into the defect zone. Safranin-O, picrosirius red staining and DIC showed tissue integration between the scaffold and injured explants. Tensile properties of injured explants treated with PDGF-BB coated scaffold were significantly higher than in the scaffold without PDGF. In conclusion, PDGF-BB-coated scaffold increased PDGFR? expression and promoted migration of endogenous meniscus cells to the defect area. New matrix was formed that bridged the space between the native meniscus and the scaffold and this was associated with improved biomechanical properties. The PDGF-BB-coated scaffold will be promising for clinical translation to healing of meniscus tears. STATEMENT OF SIGNIFICANCE:Meniscus tears are the most common injury of the knee joint. The most prevalent forms that occur in the inner third typically do not spontaneously heal and represent a major risk factor for the development of knee osteoarthritis. The goal of this project was to develop an approach that is readily applicable for clinical use. We selected a natural and readily available decellularized meniscus scaffold and conjugated it with PDGF, which we had previously found to have strong chemotactic activity for chondrocytes and progenitor cells. The present results show that insertion of the PDGF-conjugated scaffold in defects in avascular meniscus led to endogenous cell migration and proliferation into the defect zone with tissue integration between the scaffold and injured explants and improved tensile properties. This PDGF-conjugated scaffold will be promising for a translational approach to healing of meniscus tears.

SUBMITTER: Lee KI

PROVIDER: S-EPMC6090559 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Platelet-derived growth factor-coated decellularized meniscus scaffold for integrative healing of meniscus tears.

Lee Kwang Il KI Olmer Merissa M Baek Jihye J D'Lima Darryl D DD Lotz Martin K MK

Acta biomaterialia 20180614

The aim of this study was to examine the potential of platelet-derived growth factor (PDGF)-coated decellularized meniscus scaffold in mediating integrative healing of meniscus tears by inducing endogenous cell migration. Fresh bovine meniscus was chemically decellularized and covalently conjugated with heparin and PDGF-BB. In vitro PDGF release kinetics was measured. The scaffold was transplanted into experimental tears in avascular bovine meniscus explants and cultured for 2 and 4 weeks. The n ...[more]

PMID: 29908335

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Project description:Meniscus injuries are extremely common with approximately one million patients undergoing surgical treatment annually in the U.S. alone, but no regenerative therapy exist. Previously, we showed that controlled applications of connective tissue growth factor (CTGF) and transforming growth factor beta 3 (TGFβ3) via fibrin-based bio-glue facilitate meniscus healing by inducing recruitment and stepwise differentiation of synovial mesenchymal stem/progenitor cells. Here, we first explored the potential of genipin, a natural crosslinker, to enhance fibrin-based glue's mechanical and degradation properties. In parallel, we identified the harmful effects of lubricin on meniscus healing and investigated the mechanism of lubricin deposition on the injured meniscus surface. We found that the pre-deposition of hyaluronic acid (HA) on the torn meniscus surface mediates lubricin deposition. Then we implemented chemical modifications with heparin conjugation and CD44 on our bioactive glue to achieve strong initial bonding and integration of lubricin pre-coated meniscal tissues. Our data suggested that heparin conjugation significantly enhances lubricin-coated meniscal tissues. Similarly, CD44, exhibiting a strong binding affinity to lubricin and hyaluronic acid (HA), further improved the integrated healing of HA/lubricin pre-coated meniscus injuries. These findings may represent an important foundation for developing a translational bio-active glue guiding the regenerative healing of meniscus injuries. Graphical abstract Image 1 Highlights • We demonstrated an optimal genipin cross-linking to promote physical properties of bioactive glue for meniscus healing.• Clinically relevant lubricin infiltration into meniscus injuries showed harmful effect on integrated meniscus healing.• Chemical modifications with heparin achieved a strong bonding and integration of lubricin pre-coated meniscal tissues.• CD44, exhibiting a strong binding affinity to lubricin and hyaluronic acid (HA), further improved the tissue integration .• These findings represent an important foundation for a translational bio-active glue meniscus regeneration.

Project description:PurposeTo perform a systematic review on clinical and radiologic outcomes for meniscus tears treated nonoperatively with platelet-rich plasma (PRP).MethodsA literature search was performed according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using keywords and Boolean operators in SCOPUS, PubMed, Medline, and the Cochrane Central Register for Controlled Trials in April 2023. Inclusion criteria were limited to Level I to IV human studies reporting on outcomes of meniscus tears treated nonoperatively with PRP.ResultsA total of 6 studies, consisting of 184 patients, were identified. There was 1 Level I study and 5 Level IV studies. Mean patient age was 47.8 ± 7.9 years, with 62% (n = 114/184) being female. The medial meniscus was treated in 95.7% (n = 157/164) of patients. Mean follow-up ranged from 75.9 days to 31.9 months. Meniscus tears were generally described as chronic, degenerative, or intrasubstance. In 4 studies, magnetic resonance imaging revealed variable improvement in meniscus grade with complete healing in 0% to 44% of patients and partial healing in 0% to 40% of patients. Four of 5 studies reported significant statistical improvement in pain from baseline to final follow-up. Studies reporting on clinical outcomes showed significant improvements Lysholm score (2 studies), Knee injury and Osteoarthritis Outcome Score total score (2 studies), and Tegner score (1 study). Successful return to sport occurred in 60% to 100% of patients. Two studies reported that most patients were either very satisfied or satisfied following treatment.ConclusionsThe use of PRP injections for the treatment of meniscus tears led to variable results based on postoperative magnetic resonance evaluation and improvements in clinical outcomes, although the clinical significance remains unclear. The heterogeneity of PRP protocols, short-term follow-up, and lack of comparative studies limit findings.Level of evidenceLevel IV, systematic review of Level I to IV studies.

Project description:IntroductionSilk fibroin (SF) scaffolds have been shown to be a suitable substrate for tissue engineering and to improve tissue regeneration when cellularized with mesenchymal stromal cells (MSCs). We here demonstrate, for the first time, that electrospun nanofibrous SF patches cellularized with human adipose-derived MSCs (Ad-MSCs-SF), or decellularized (D-Ad-MSCs-SF), are effective in the treatment of skin wounds, improving skin regeneration in db/db diabetic mice.MethodsThe conformational and structural analyses of SF and D-Ad-MSCs-SF patches were performed by scanning electron microscopy, confocal microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. Wounds were performed by a 5 mm punch biopsy tool on the mouse's back. Ad-MSCs-SF and D-Ad-MSCs-SF patches were transplanted and the efficacy of treatments was assessed by measuring the wound closure area, by histological examination and by gene expression profile. We further investigated the in vitro angiogenic properties of Ad-MSCs-SF and D-Ad-MSCs-SF patches by affecting migration of human umbilical vein endothelial cells (HUVECs), keratinocytes (KCs) and dermal fibroblasts (DFs), through the aortic ring assay and, finally, by evaluating the release of angiogenic factors.ResultsWe found that Ad-MSCs adhere and grow on SF, maintaining their phenotypic mesenchymal profile and differentiation capacity. Conformational and structural analyses on SF and D-Ad-MSCs-SF samples, showed that sterilization, decellularization, freezing and storing did not affect the SF structure. When grafted in wounds of diabetic mice, both Ad-MSCs-SF and D-Ad-MSCs-SF significantly improved tissue regeneration, reducing the wound area respectively by 40% and 35%, within three days, completing the process in around 10 days compared to 15-17 days of controls. RT2 gene profile analysis of the wounds treated with Ad-MSCs-SF and D-Ad-MSCs-SF showed an increment of genes involved in angiogenesis and matrix remodeling. Finally, Ad-MSCs-SF and D-Ad-MSCs-SF co-cultured with HUVECs, DFs and KCs, preferentially enhanced the HUVECs' migration and the release of angiogenic factors stimulating microvessel outgrowth in the aortic ring assay.ConclusionsOur results highlight for the first time that D-Ad-MSCs-SF patches are almost as effective as Ad-MSCs-SF patches in the treatment of diabetic wounds, acting through a complex mechanism that involves stimulation of angiogenesis. Our data suggest a potential use of D-Ad-MSCs-SF patches in chronic diabetic ulcers in humans.

Dataset Information

Platelet-derived growth factor-coated decellularized meniscus scaffold for integrative healing of meniscus tears.

Publications

Platelet-derived growth factor-coated decellularized meniscus scaffold for integrative healing of meniscus tears.

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