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Related Articles [Experimental research on repair of rabbit articular cartilage deffects with composite of autologous cell-carriers]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2008 Apr;22(4):487-91 Authors: Bai T, Shu J, Wang J, Lu J, Li W, Pu B Abstract OBJECTIVE: To study the effect of the repair of rabbit articular cartilage defects by the composite of chondrogenic induction of autologous MSCs and autologous "two-phase" bone matrix gelatin (BMG). METHODS: Twenty-four healthy adult New Zealand rabbits weighing 2 to 3 kg were divided into group A, B and C with 8 in each. Autologous MSCs derived from group A were cultured in vitro and observed under inverted phase contrast microscope when enough cells through trypsinization transferring in vitro were obtained. Then the growth curves of 1, 3 and 5 passage culture of MSCs were drawn. The 3rd passage MSCs were induced into chondrogenic differentiation by adding TGF-beta1 (10 ng/mL), IGF-1 (10 ng/mL) and vitamin C (50 ng/mL) in vitro. At 8 days after induction, the features of chondrocytes were observed under inverted phase contrast microscope,and immunohistochemical staining and Mallory staining were made. Getting out part of the ilium of group A and B, according to the method of Urist, the "two-phase" BMG was acquired. Chondrogenic induction of autologous MSCs was inoculated into the corresponding BMG to set up a composite of cell-carrier, and then it was observed through scanning electric microscope after 3 days of culture. The model of articular cartilage defects of rabbits was made: in group A,autologous cell-carriers were implanted; in group B, there only existed autologous BMG; in group C,there was nothing. At 8, 12 weeks after operation, the gross, HE staining and immunohistochemical staining were made,and grading scales were evaluated according to Wakitani histological grading method. RESULTS: Features of MSCs were as follows: the shape of primary cells was shot-spindled and of passage cells was long. As to the growth curves of 1, 3 and 5 passage culture of MSCs,passage cells grew slowly for 3 days after being passaged and went into log-growth during the 3rd and the 7th days and into plateau later, but the 3rd passage cells grew best. Observation of MSCs after chondrogenic induction was performed: the shape of cells was elliptical and the effect of induction was verified by the positive results of collagen type II, S-100 and Mallory staining. Under scanning electric microscope,the structure of BMG was good and cells were observed growing in it well. As far as repair of articular cartilage defects are concerned at 8, 12 weeks after transplantation, the defects in group A were repaired by the hyline-like tissue and the structures of the cartilage surface and normal cartilage were in integrity,and immunohistochemical staining of collagen type II was positive, while those in group B and C were repaired by the fibrous-like tissues and the surfaces were irregular. In Wakitanni histological score, at 8 weeks after operation, group A was (3.50 +/- 1.51) points, group B was (10.00 +/- 1.41) points and group C was (12.00 +/- 0.93) points; at 12 weeks, group A was (1.13 +/- 0.99) points, group B was (8.38+/-1.30) points, and group C was (10.13 +/- 1.64) points. At different time points,group A was significantly better than group B and C, showing significant differences (P < 0.05). CONCLUSION: Induced autologous MSCs and the composite withautologous "two-phase" BMG have the function to repair articular cartilage defects, and they are better than autologous BMG transplanted only or nothing transplanted. PMID: 18575455 [PubMed - indexed for MEDLINE]
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Related Articles Tissue engineering of cartilage: the road a group of researchers have traveled. J Orthop Sci. 2008 Jul;13(4):396-8 Authors: Liu HC PMID: 18696203 [PubMed - indexed for MEDLINE]
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Related Articles [Current treatment for cartilage damage in the patellofemoral joint]. Orthopade. 2008 Sep;37(9):841-7 Authors: Steinwachs MR, Kreuz PC, Guhlke-Steinwachs U, Niemeyer P Abstract Joint cartilage damage in adults has practically no tendency to self healing. Symptomatic grade III/IV damage requires surgical treatment. There are special challenges involved in cartilage damage in the patellofemoral joint as the complicated biomechanics of the joint is often combined with dysplasia. All tissue regeneration measures are based on the recruitment of cells. The synovial cells available in the joint can be differentiated to fibrous cartilage under certain mechanical conditions; however, they cannot sufficiently fill in defects. Also the use of bone marrow cells for cartilage reconstruction only creates mechanically inferior fibrous cartilage (Pridie drillings, microfracture, AMIC). Presently only cultivated, autologous chondrocytes from the lab are available for a biomechanically high-quality reconstruction of the cartilage layer.The application of mesenchymal stem cells is a subject of extensive international research. However, the first experimental studies, after initial formation of cartilage, disappointingly show significant ossification. Essential conditions for a successful treatment of patellofemoral cartilage damage are the diagnosis of accompanying pathological conditions, selection of the right cartilage-regenerating procedure, sufficient removal of the basic pathological defect, and implementation of standardized rehabilitation. PMID: 18719889 [PubMed - indexed for MEDLINE]
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Related Articles Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypotheses. 2008 Dec;71(6):900-8 Authors: Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D Abstract Mesenchymal stem cells are pluripotent cells found in multiple human tissues including bone marrow, synovial tissues, and adipose tissues. They have been shown to differentiate into bone, cartilage, muscle, and adipose tissue and represent a possible promising new therapy in regenerative medicine. Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone. The regeneration of articular cartilage via percutaneous introduction of mesenchymal stem cells (MSC's) is a topic of significant scientific and therapeutic interest. Current treatment for cartilage damage in osteoarthritis focuses on surgical interventions such as arthroscopic debridement, microfracture, and cartilage grafting/transplant. These procedures have proven to be less effective than hoped, are invasive, and often entail a prolonged recovery time. We hypothesize that autologous mesenchymal stem cells can be harvested from the iliac crest, expanded using the patient's own growth factors from platelet lysate, then successfully implanted to increase cartilage volume in an adult human knee. We present a review highlighting the developments in cellular and regenerative medicine in the arena mesenchymal stem cell therapy, as well as a case of successful harvest, expansion, and transplant of autologous mesenchymal stem cells into an adult human knee that resulted in an increase in meniscal cartilage volume. PMID: 18786777 [PubMed - indexed for MEDLINE]
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Related Articles [Experimental study on neural stem cell transplantation delaying denervated muscle atrophy]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2008 Sep;22(9):1051-5 Authors: Shen Y, Xu J, Xu W, Xu L, Lu J, Gu Y Abstract OBJECTIVE: To observe the delaying effect of neural stem cell (NSC) transplantation on denervated muscle atrophy after peripheral nerve injury, and to investigate its mechanism. METHODS: NSCs were separated from the spinal cords of green fluorescent protein (GFP) transgenic rats aged 12-14 days mechanically and were cultured and induced to differentiate in vitro. Thirty-two F344 rats, aged 2 months and weighed (180 +/- 20) g, were randomized into two groups (n=16 per group). The animal models of denervated musculus triceps surae were established by transecting right tibial nerve and common peroneal nerve 1.5 cm above the knee joints. In the experimental and the control group, 5 microL of GFP-NSC suspension and 5 microL of culture supernatant were injected into the distal stump of the tibial nerve, respectively. The general condition of rats after operation was observed. At 4 and 12 weeks postoperatively, the wet weight of right musculus triceps surae was measured, the HE staining, the Mallory trichrome staining and the postsynaptic membrane staining were adopted for the histological observation. Meanwhile, the section area of gastrocnemius fiber and the area of postsynaptic membrane were detected by image analysis software and statistical analysis. RESULTS: The wounds in both groups of animals healed by first intension, no ulcer occurred in the right hind limbs. At 4 and 12 weeks postoperatively, the wet weight of right musculus triceps surae was (0.849 +/- 0.064) g and (0.596 +/- 0.047) g in the experimental group, respectively, and was (0.651 +/- 0.040) g and (0.298 +/- 0.016) g in the control group, respectively, showing a significant difference (P < 0.05). The fiber section area of the gastrocnemius was 72.55% +/- 8.12% and 58.96% +/- 6.07% in the experimental group, respectively, and was 50.23% +/- 4.76% and 33.63% +/- 4.41% in the control group, respectively. There were significant differences between them (P < 0.05). Mallory trichrome staining of muscle notified that there was more collagen fiber hyperplasia of denervated gastrocnemius in the control group than that in the experimental group at 4 and 12 weeks postoperatively. After 12 weeks of operation, the area of postsynaptic membrane in the experimental group was (137.29 +/- 29.14) microm2, which doubled that in the control group as (61.03 +/- 11.38) microm2 and was closer to that in normal postsynaptic membrane as (198.63 +/- 23.11) microm2, showing significant differences (P < 0.05). CONCLUSION: The transplantation in vivo of allogenic embryonic spinal cord NSCs is capable of delaying denervated muscle atrophy and maintaining the normal appearance of postsynaptic membrane, providing a new approach to prevent and treat the denervated muscle atrophy clinically. PMID: 18822726 [PubMed - indexed for MEDLINE]
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Related Articles Cartilage repair: synthetics and scaffolds: basic science, surgical techniques, and clinical outcomes. Sports Med Arthrosc. 2008 Dec;16(4):208-16 Authors: Kerker JT, Leo AJ, Sgaglione NA Abstract Symptomatic articular cartilage lesions have gained attention and clinical interest in recent years and can be difficult to treat. Historically, various biologic surgical treatment options have yielded inconsistent results because of the inferior biomechanical properties associated with a variable healing response. Improving technology and surgical advances has generated considerable research in cartilage resurfacing and optimizing hyaline tissue restoration. Biologic innovation and tissue engineering in cartilage repair have used matrix scaffolds, autologous and allogenic chondrocytes, cartilage grafts, growth factors, stem cells, and genetic engineering. Numerous evolving technologies and surgical approaches have been introduced into the clinical setting. This review will discuss the basic science, surgical techniques, and clinical outcomes of novel synthetic materials and scaffolds for articular cartilage repair. PMID: 19011552 [PubMed - indexed for MEDLINE]
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Related Articles Emerging technologies and fourth generation issues in cartilage repair. Sports Med Arthrosc. 2008 Dec;16(4):246-54 Authors: Kessler MW, Ackerman G, Dines JS, Grande D Abstract The goals of successful cartilage repair include reducing pain, improving symptoms, and long-term function; preventing early osteoarthritis and subsequent total knee replacements; and rebuilding hyaline cartilage instead of fibrous tissue. Current methods such as microfracture, osteoarticular autograft transfer system, mosaicplasty, and autologous chondrocyte implantation are somewhat successful in regenerating cartilage; however, they also have significant limitations. The future of fourth generation cartilage repair focuses on gene therapy, the use of stem cells (bone marrow, adipose, or muscle derived), and tissue engineering. Emerging techniques include creating elastin-like polymers derived from native elastin sequences to serve as biocompatible scaffolds; using hydrogels to obtain a homogeneous distribution of cells within a 3-dimensional matrix; and using nonviral gene delivery via nucleofection to allow mesenchymal stem cells the ability to express osteogenic growth factors. Although many of the techniques mentioned have yet to be used in a cartilage regeneration model, we have tried to anticipate how methods used in other specialties may facilitate improved cartilage repair. PMID: 19011557 [PubMed - indexed for MEDLINE]
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Related Articles Repair of full-thickness femoral condyle cartilage defects using allogeneic synovial cell-engineered tissue constructs. Osteoarthritis Cartilage. 2009 Jun;17(6):714-22 Authors: Pei M, He F, Boyce BM, Kish VL Abstract OBJECTIVE: Synovium-derived stem cells (SDSCs) have proven to be superior in cartilage regeneration compared with other sources of mesenchymal stem cells. We hypothesized that conventionally passaged SDSCs can be engineered in vitro into cartilage tissue constructs and the engineered premature tissue can be implanted to repair allogeneic full-thickness femoral condyle cartilage defects without immune rejection. METHODS: Synovial tissue was harvested from rabbit knee joints. Passage 3 SDSCs were mixed with fibrin glue and seeded into non-woven polyglycolic acid (PGA) mesh. After 1-month incubation with growth factor cocktails, the premature tissue was implanted into rabbit knees to repair osteochondral defects with Collagraft as a bone substitute in the Construct group. Fibrin glue-saturated PGA/Collagraft composites were used as a Scaffold group. The defect was left untreated as an Empty group. RESULTS: SDSCs were engineered in rotating bioreactor systems into premature cartilage, which displayed the expression of sulfated glycosaminoglycan (GAG), collagen II, collagen I, and macrophages. Six months after implantation with premature tissue, cartilage defects were full of smooth hyaline-like cartilage with no detectable collagen I and macrophages but a high expression of collagen II and GAG, which were also integrated with the surrounding native cartilage. The Scaffold and Empty groups were resurfaced with fibrous-like and fibrocartilage tissue, respectively. CONCLUSION: Allogeneic SDSC-based premature tissue constructs are a promising stem cell-based approach for cartilage defects. Although in vitro data suggest that contaminated macrophages affected the quality of SDSC-based premature cartilage, effects of macrophages on in vivo tissue regeneration and integration necessitate further investigation. PMID: 19128988 [PubMed - indexed for MEDLINE]
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Related Articles [Preliminary studies on repairing osteochondral defects in the rabbit knee joint by using porous PA66/n-HA combination mesenchymal stem cells]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2008 Dec;25(6):1349-53 Authors: Wu J, Yang T, Liu Y, Guo T, Mu Y, Li Y Abstract We have investigated the effects of repairing knee osteochondral defects in rabbit by using porous polyamide 66/nano-Hydroxyapatite (PA66/n-HA) combination bone marrow mesenchymal stem cells (MSCs). Eighteen 6-month-old New Zealand rabbits were used to produce the models of 4 mm x 4 mm osteochondral defect in the middle trochlea groove of femur. These models were randomly divided into 3 groups: PA66/n-HA + MSCs Group (Group A), PA66/n-HA group (Group B) and Operation control-group (Group C) in which operation for osteochondral defects was performed but neither material nor cells were implanted. The materials in Group A were seeded with MSCs (5 x 10(5)) in vitro before being implanted in to defects. The materials in groups A and B were 0.5 - 0.8 mm lower than normal cartilage. The animals were killed 1 and 4 months after operation. We assessed the effects by means of macroscopic observation, HE staining, toluidine blue staining, immunohistochemistry assay for type I and type II collagen. Group A displayed a little effect at the 1 month, but at the 4th month, Group A showed better results,compared to Groups B and C. At this time point, the repair tissue of Group A was regular; it presented more metachromatic substance visualized by toluidine blue staining, and it expressed type II collagen(+ +) and type I collagen(+). These results demonstrate that the repair tissue in Group A is nearly hyaline cartilage. So we presume that porous PA66/n-HA provides biomechanical support, and at the same time, MSCs enhance the repair effects. PMID: 19166207 [PubMed - indexed for MEDLINE]
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Related Articles Biological approaches for cartilage repair. J Knee Surg. 2009 Jan;22(1):36-44 Authors: Gobbi A, Bathan L Abstract The social impact of bone and cartilage pathologies entails high costs in terms of therapeutic treatments and loss of income. As a result, the current research trend includes preventive interventions and therapeutic solutions that can lead to an enhancement of tissue regeneration and the reduction of degenerative mechanisms. Many options have been made available to address problems regarding cartilage damage, each with its own advantages and disadvantages. Several studies are currently in progress to clarify some of the questions that remain unanswered about the long-term durability of these procedures and the possible modifications that can be made to achieve better results. Biotechnology is progressing at a rapid pace that allows the introductions of several products for clinical application; however, randomized, prospective studies for these innovations should be conducted to validate the safety and efficacy of cartilage regeneration. PMID: 19216352 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell-based therapy for cartilage repair: a review. Knee Surg Sports Traumatol Arthrosc. 2009 Nov;17(11):1289-97 Authors: Koga H, Engebretsen L, Brinchmann JE, Muneta T, Sekiya I Abstract Articular cartilage injury remains one of the major concerns in orthopaedic surgery. Mesenchymal stem cell (MSC) transplantation has been introduced to avoid some of the side effects and complications of current techniques. The purpose of this paper is to review the literature on MSC-based cell therapy for articular cartilage repair to determine if it can be an alternative treatment for cartilage injury. MSCs retain both high proliferative potential and multipotentiality, including chondrogenic differentiation potential, and a number of successful results in transplantation of MSCs into cartilage defects have been reported in animal studies. However, the use of MSCs for cartilage repair is still at the stage of preclinical and phase I studies, and no comparative clinical studies have been reported. Therefore, it is difficult to make conclusions in human studies. This requires randomized clinical trials to evaluate the effectiveness of MSC-based cell therapy for cartilage repair. PMID: 19333576 [PubMed - indexed for MEDLINE]
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Related Articles Tissue engineering: use of scaffolds for ligament and tendon healing and regeneration. Knee Surg Sports Traumatol Arthrosc. 2009 Jun;17(6):559-60 Authors: Woo SL PMID: 19350224 [PubMed - indexed for MEDLINE]
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Related Articles Intra-articular Injected synovial stem cells differentiate into meniscal cells directly and promote meniscal regeneration without mobilization to distant organs in rat massive meniscal defect. Stem Cells. 2009 Apr;27(4):878-87 Authors: Horie M, Sekiya I, Muneta T, Ichinose S, Matsumoto K, Saito H, Murakami T, Kobayashi E Abstract Osteoarthritis in the knees, which can be caused by meniscal defect, constitutes an increasingly common medical problem. Repair for massive meniscal defect remains a challenge owing to a lack of cell kinetics for the menisci precursors in knee joint. The synovium plays pivotal roles during the natural course of meniscal healing and contains mesenchymal stem cells (MSCs) with high chondrogenic potential. Here, we investigated whether intra-articular injected synovium-MSCs enhanced meniscal regeneration in rat massive meniscal defect. To track the injected cells, we developed transgenic rats expressing dual luciferase (Luc) and LacZ. The cells derived from synovium of the rats demonstrated colony-forming ability and multipotentiality, both characteristics of MSCs. Hierarchical clustering analysis revealed that gene expression of meniscal cells was closer to that of synovium-MSCs than to that of bone marrow-MSCs. Two to 8 weeks after five million Luc/LacZ+ synovium-MSCs were injected into massive meniscectomized knee of wild-type rat, macroscopically, the menisci regenerated much better than it did in the control group. After 12 weeks, the regenerated menisci were LacZ positive, produced type 2 collagen, and showed meniscal features by transmission electron microscopy. In in-vivo luminescence analysis, photons increased in the meniscus-resected knee over a 3-day period, then decreased without detection in all other organs. LacZ gene derived from MSCs could not be detected in other organs except in synovium by real-time PCR. Synovium-MSCs injected into the massive meniscectomized knee adhered to the lesion, differentiated into meniscal cells directly, and promoted meniscal regeneration without mobilization to distant organs. PMID: 19350690 [PubMed - indexed for MEDLINE]
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Related Articles Cell-based therapy in articular cartilage lesions of the knee. Arthroscopy. 2009 May;25(5):531-52 Authors: Nakamura N, Miyama T, Engebretsen L, Yoshikawa H, Shino K Abstract PURPOSE: The purpose of this systematic review was to determine the effectiveness of cell-based therapy for articular cartilage defects of the knee. METHODS: We performed a literature search in Medline (1994 to 2009) regarding cell-based therapies for chondral lesions. RESULTS: We identified 10 Level I or II randomized controlled trials and 3 Level II prospective comparative studies. Although many of these studies had substantial flaws, which could introduce bias, we overall found no difference between the cell-based studies and other interventions. In addition, we identified 26 Level III and IV studies of cell-based therapy. CONCLUSIONS: There is insufficient evidence from the studies included in this review to say whether cell-based therapy is superior to other treatment strategies in articular cartilage lesions of the knee. PMID: 19409312 [PubMed - indexed for MEDLINE]
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Related Articles Rotator cuff repair with periosteum for enhancing tendon-bone healing: a biomechanical and histological study in rabbits. Knee Surg Sports Traumatol Arthrosc. 2009 Dec;17(12):1447-53 Authors: Chang CH, Chen CH, Su CY, Liu HT, Yu CM Abstract During rotator cuff repair surgery, fixation and incorporation of ruptured rotator cuff tendon into the bone is a major concern. The repair usually fails at the tendon-bone interface, especially in cases where the tear is massive. The periosteum contains multipotent stem cells that have the potential to differentiate into osteogenic and chondrogenic tissues, which may restore the original structure at the tendon-bone interface, fibrocartilage. In this study, we investigated the effect of periosteum on the healing of the infraspinatus tendon and bone using a clinically relevant rabbit model of rotator cuff tear. We used 36 skeletally mature New Zealand white rabbits in the study. The infraspinatus tendon at right limb was detached from greater tuberosity, and a periosteal flap taken from the proximal tibia was sutured onto the torn end of tendon. The contralateral limb, which was used as a control, received the same treatment without a periosteum. The rabbits were sacrificed at 4, 8, and 12 weeks, and the tendon-bone interface was put to histological exam and the biomechanical testing to assess strength of tendon-bone interface. Histological analysis of the tendon-bone interface revealed that the periosteum formed a fibrous layer over the interface between tendon and bone. At 4 weeks, fibrotic tissue showed progressive integration over the interface between cuff tendon and bone. At 8 weeks, progressive formation of fibrovascular tissue and fibrocartilage was observed between tendon and bone. At 12 weeks, extensive formation of fibrocartilage and bone was noted in the interface. The significant increase of failure load with time indicated a progressive increase in the tendon-bone incorporation strength. At 4 weeks after operation, the attachment strength of the limbs with the periosteum treated was higher than that of the control limbs; however, this difference was not statistically significant. At 8 and 12 weeks, a statistically significant increase was noted in the attachment strength of the limb treated with the periosteum. Most specimens failed at the tendon-bone interface (18/20). In the treatment of a torn rotator cuff in rabbit model, improved healing process with greater attachment strength could be achieved by suturing the periosteum between the end of tendon and the bone trough. Histological examination revealed that the cambium layer of the periosteum could serve as a potent interface layer and become progressively mature and organized during the healing process, resulting in fibrocartilage formation and the subsequent integration of the disrupted tendon into the bone. Biomechanical testing revealed a progressive increase in the attachment strength with time indicating the progressive tendon-bone incorporation. When performing rotator cuff repair in a large or massive tear, a periosteal flap can be sutured onto the torn end of tendon to enhance tendon-bone healing. PMID: 19440695 [PubMed - indexed for MEDLINE]
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Related Articles Enhanced early tissue regeneration after matrix-assisted autologous mesenchymal stem cell transplantation in full thickness chondral defects in a minipig model. Cell Transplant. 2009;18(8):923-32 Authors: Jung M, Kaszap B, Redöhl A, Steck E, Breusch S, Richter W, Gotterbarm T Abstract Adult mesenchymal stem cells (MSCs) are an attractive cell source for new treatment strategies in regenerative medicine. This study investigated the potential effect of matrix assisted MSC transplantation for articular cartilage regeneration in a large-animal model 8 weeks postoperatively. MSCs from bone marrow aspirates of eight Goettingen minipigs were isolated and expanded prior to surgery. Articular cartilage defects of 5.4 mm were created bilaterally in the medial patellar groove without penetrating the subchondral bone plate. Defects were either left empty (n = 4), covered with a collagen type I/III membrane (n = 6) or additionally treated with autologous MSC transplantation (2 x 10(6); n = 6). After 8 weeks animals were euthanized and the defect area was assessed for its gross appearance. Histomorphological analysis of the repair tissue included semiquantitative scoring (O'Driscoll score) and quantitative histomorphometric analysis for its glycosaminoglycan (GAG) and collagen type II content. All membranes were found to cover the defect area 8 weeks postoperatively. Median defect filling was 115.8% (membrane), 117.8% (empty), and 100.4% (MSC), respectively (not significant). Histomorphological scoring revealed significantly higher values in MSC-treated defects (median 16.5) when compared to membrane treatment (median 9.5) or empty defects (median 11.5; p = 0.015 and p = 0.038). Histomorphometric analysis showed larger GAG/collagen type II-positive areas in the MSC-treated group (median 24.6%/29.5% of regeneration tissue) compared to 13.6%/33.1% (empty defects) and 1.7%/6.2% (membrane group; p = 0.066). Cell distribution was more homogeneous in MSC compared to membrane-only group, where cells were found mainly near the subchondral zone. In conclusion, autologous matrix-assisted MSC transplantation significantly increased the histomorphological repair tissue quality during early articular cartilage defect repair and resulted in higher GAG/collagen type II-positive cross-sectional areas of the regenerated tissue. PMID: 19523325 [PubMed - indexed for MEDLINE]
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Related Articles [Regenerative medicine in orthopaedics. Cell therapy - tissue engineering - in situ regeneration]. Orthopade. 2009 Sep;38(9):859-67; quiz 868-9 Authors: Richter W, Diederichs S Abstract Therapeutic approaches in regenerative medicine, irrespective of specific fields, comprise cell therapy, tissue engineering and in situ regeneration. Regenerative orthopaedics often leads the way on the path to clinical application. In cell therapy primary cells could be replaced by adult mesenchymal stem cells exhibiting almost unlimited regeneration capacity. More sophisticated biomaterial design allowing specific control of cell morphology and tissue organisation is the current focus of advancements in tissue engineering, while signalling to cells by intelligent biomaterials is a main focus of in situ regeneration. These new approaches to the reconstruction of structures and function in damaged or dysfunctional tissue will make it more often possible to achieve a sustainable improvement in terms of real regeneration rather than an acceptable repair. PMID: 19657618 [PubMed - indexed for MEDLINE]
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Related Articles Morphological and functional characteristics of three-dimensional engineered bone-ligament-bone constructs following implantation. J Biomech Eng. 2009 Oct;131(10):101017 Authors: Ma J, Goble K, Smietana M, Kostrominova T, Larkin L, Arruda EM Abstract The incidence of ligament injury has recently been estimated at 400,000/year. The preferred treatment is reconstruction using an allograft, but outcomes are limited by donor availability, biomechanical incompatibility, and immune rejection. The creation of an engineered ligament in vitro solely from patient bone marrow stromal cells (has the potential to greatly enhance outcomes in knee reconstructions. Our laboratory has developed a scaffoldless method to engineer three-dimensional (3D) ligament and bone constructs from rat bone marrow stem cells in vitro. Coculture of these two engineered constructs results in a 3D bone-ligament-bone (BLB) construct with viable entheses, which was successfully used for medial collateral ligament (MCL) replacement in a rat model. 1 month and 2 month implantations were applied to the engineered BLBs. Implantation of 3D BLBs in a MCL replacement application demonstrated that our in vitro engineered tissues grew and remodeled quickly in vivo to an advanced phenotype and partially restored function of the knee. The explanted 3D BLB ligament region stained positively for type I collagen and elastin and was well vascularized after 1 and 2 months in vivo. Tangent moduli of the ligament portion of the 3D BLB 1 month explants increased by a factor of 2.4 over in vitro controls, to a value equivalent to those observed in 14-day-old neonatal rat MCLs. The 3D BLB 1 month explants also exhibited a functionally graded response that closely matched native MCL inhomogeneity, indicating the constructs functionally adapted in vivo. PMID: 19831487 [PubMed - indexed for MEDLINE]
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Related Articles Quality of newly formed cartilaginous tissue in defects of articular surface after transplantation of mesenchymal stem cells in a composite scaffold based on collagen I with chitosan micro- and nanofibres. Physiol Res. 2010;59(4):605-14 Authors: Necas A, Plánka L, Srnec R, Crha M, Hlucilová J, Klíma J, Starý D, Kren L, Amler E, Vojtová L, Jancár J, Gál P Abstract The aim of this study was to evaluate macroscopically, histologically and immunohistochemically the quality of newly formed tissue in iatrogenic defects of articular cartilage of the femur condyle in miniature pigs treated with the clinically used method of microfractures in comparison with the transplantation of a combination of a composite scaffold with allogeneic mesenchymal stem cells (MSCs) or the composite scaffold alone. The newly formed cartilaginous tissue filling the defects of articular cartilage after transplantation of the scaffold with MSCs (Group A) had in 60 % of cases a macroscopically smooth surface. In all lesions after the transplantation of the scaffold alone (Group B) or after the method of microfractures (Group C), erosions/fissures or osteophytes were found on the surface. The results of histological and immunohistochemical examination using the modified scoring system according to O'Driscoll were as follows: 14.7+/-3.82 points after transplantations of the scaffold with MSCs (Group A); 5.3+/-2.88 points after transplantations of the scaffold alone (Group B); and 5.2+/-0.64 points after treatment with microfractures (Group C). The O'Driscoll score in animals of Group A was significantly higher than in animals of Group B or Group C (p<0.0005 both). No significant difference was found in the O'Driscoll score between Groups B and C. The treatment of iatrogenic lesions of the articular cartilage surface on the condyles of femur in miniature pigs using transplantation of MSCs in the composite scaffold led to the filling of defects by a tissue of the appearance of hyaline cartilage. Lesions treated by implantation of the scaffold alone or by the method of microfractures were filled with fibrous cartilage with worse macroscopic, histological and immunohistochemical indicators. PMID: 19929138 [PubMed - indexed for MEDLINE]
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Related Articles Augmentation of degenerated human cartilage in vitro using magnetically labeled mesenchymal stem cells and an external magnetic device. Arthroscopy. 2009 Dec;25(12):1435-41 Authors: Kobayashi T, Ochi M, Yanada S, Ishikawa M, Adachi N, Deie M, Arihiro K Abstract PURPOSE: The purpose of this study was to investigate whether it is possible to regenerate degenerated human cartilage in vitro by use of magnetically labeled mesenchymal stem cells (MSCs) and an external magnetic device. METHODS: MSCs from human bone marrow were cultured and magnetically labeled. Degenerated human cartilage was obtained during total knee arthroplasty. The osteochondral fragments were attached to the sidewall of tissue culture flasks, and magnetically labeled MSCs were injected into the flasks. By use of an external magnetic device, a magnetic force was applied for 6 hours to the direction of the cartilage, and then the degenerated cartilage was cultured in chondrogenic differentiation medium for 3 weeks. In the control group a magnetic force was not applied. The specimens were evaluated histologically. RESULTS: A cell layer was formed on the degenerated cartilage as shown by H&E staining. The cell layer was also stained in toluidine blue and safranin O and with anti-collagen type II immunostaining, indicating that the cell layer contained an extracellular matrix. In the control group a cell layer was not observed on the cartilage. CONCLUSIONS: We were able to show that our system could deliver MSCs onto degenerated human cartilage and then form an extracellular matrix on the degenerated cartilage in vitro. CLINICAL RELEVANCE: Our novel cell delivery system using magnetic force may lead toward a new treatment option for osteoarthritis. PMID: 19962071 [PubMed - indexed for MEDLINE]
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Related Articles Treatment of articular cartilage lesions of the knee joint using a modified AMIC technique. Knee Surg Sports Traumatol Arthrosc. 2010 Apr;18(4):509-13 Authors: Pascarella A, Ciatti R, Pascarella F, Latte C, Di Salvatore MG, Liguori L, Iannella G Abstract This study describes a modified AMIC technique consisting of perforations according to Pridie, rather than microfractures, and the covering of the focus of the lesion with a biological collagen patch enriched with bone marrow blood drawn through the knee itself. This technique allows advantages of both the Pridie technique and the in situ proliferation of mesenchymal cells beneath a biological collagen membrane, 'augmented', with bone marrow blood. The collagen membrane forms the roof of a 'biological chamber', and serves to protect and contains the stem cells as they differentiate into chondrocytes, which will form a healthy regenerative cartilage. PMID: 20012016 [PubMed - indexed for MEDLINE]
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Related Articles Current cell-based strategies for knee cartilage injuries. J Stem Cells. 2010;5(4):177-85 Authors: Jaiswal PK, Wong K, Khan WS Abstract Cartilage is frequently damaged and shows little or no capacity for repair. Injuries that extend to the subchondral level show some capacity for repair due to the release of bone marrow derived mesenchymal stem cells. This technique is employed in techniques like the microfracture but they are only appropriate for smaller cartilage defects. Autologous Chondrocyte Implantation (ACI) and Matrix-carried Autologous Chondrocyte Implantation (MACI) are currently used in clinical practice to treat larger full thickness chondral defects in the knee with similar results. MACI does however have a number of advantages including its amenability to be performed arthroscopically or through a more limited approach without requiring arthrotomy. More definitive studies showing the long-term effects of the two cell-based treatments and comparing them are however awaited. There are a small number of studies using mesenchymal stem cells and further in vitro and in vivo studies are needed before this treatment is optimised. This review discussed these treatment options and provides an evidence-based approach to current clinical treatments. PMID: 22314866 [PubMed - indexed for MEDLINE]
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Related Articles Repair of meniscal cartilage white zone tears using a stem cell/collagen-scaffold implant. Biomaterials. 2010 Mar;31(9):2583-91 Authors: Pabbruwe MB, Kafienah W, Tarlton JF, Mistry S, Fox DJ, Hollander AP Abstract Injuries to the avascular region of knee meniscal cartilage do not heal spontaneously. To address this problem we have developed a new stem cell/collagen-scaffold implant system in which human adult bone marrow mesenchymal stem cells are seeded onto a biodegradable scaffold that allows controlled delivery of actively dividing cells to the meniscus surface. Sandwich constructs of two white zone ovine meniscus discs with stem cell/collagen-scaffold implant in between were cultured in vitro for 40 days. Histomorphometric analysis revealed superior integration in the stem cell/collagen-scaffold groups compared to the cell-free collagen membrane or untreated controls. The addition of TGF-beta1 to differentiate stem cells to chondrocytes inhibited integration. Biomechanical testing demonstrated a significant 2-fold increase in tensile strength in all constructs using the stem cell/collagen-scaffold compared to control groups after 40 days in culture. Integration was significantly higher when collagen membranes were used that had a more open/spongy structure adjacent to both meniscal cartilage surfaces, whereas a collagen scaffold designed for osteoinduction failed to induce any integration of meniscus. In conclusion, the stem cell/collagen-scaffold implant is a potential therapeutic treatment for the repair of white zone meniscal cartilage tears. PMID: 20053438 [PubMed - indexed for MEDLINE]
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Related Articles Failure of xenoimplantation using porcine synovium-derived stem cell-based cartilage tissue constructs for the repair of rabbit osteochondral defects. J Orthop Res. 2010 Aug;28(8):1064-70 Authors: Pei M, Yan Z, Shoukry M, Boyce BM Abstract The use of xenogeneic tissues offers many advantages with respect to availability, quality control, and timing of tissue harvest. Our previous study indicated that implantation of premature tissue constructs from allogeneic synovium-derived stem cells (SDSCs) facilitated cartilage tissue regeneration. The present study investigated the feasibility of xenoimplantation of SDSC-based premature tissue constructs for the repair of osteochondral defects. Porcine SDSCs were mixed with fibrin gel, seeded in polyglycolic acid (PGA) scaffolds, and cultured in a rotating bioreactor system supplemented for 1 month with growth factor cocktails. The engineered porcine premature tissues were implanted to repair surgically induced osteochondral defects in the medial femoral condyles of 12 rabbits. Three weeks after surgery, the xenoimplantation group exhibited a smooth, whitish surface while the untreated control remained empty. Surprisingly, 6 months after surgery, the xenoimplantation group displayed some tissue loss while the untreated control group was overgrown with fibrocartilage tissue. In the xenoimplantation group, chronic inflammation was observed in synovial tissue where porcine major histocompatibility complex (MHC) class II antigen positively stained in the engulfed foreign bodies. In addition, porcine source cells also migrated from the implantation site and may have been responsible for the observed loss of glycosaminoglycans (GAGs) underneath surrounding articular cartilage. The histological score was much worse in the xenoimplanted group than in the untreated control. Our study suggested that SDSC-based xenogeneic tissue constructs might cause delayed immune rejection. Xenotransplantation may not be an appropriate approach to repair osteochondral defects. PMID: 20140938 [PubMed - indexed for MEDLINE]
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Related Articles Management of articular cartilage defects of the knee. J Bone Joint Surg Am. 2010 Apr;92(4):994-1009 Authors: Bedi A, Feeley BT, Williams RJ Abstract Articular cartilage has a poor intrinsic capacity for healing. The goal of surgical techniques to repair articular cartilage injuries is to achieve the regeneration of organized hyaline cartilage. Microfracture and other bone marrow stimulation techniques involve penetration of the subchondral plate in order to recruit mesenchymal stem cells into the chondral defect. The formation of a stable clot that fills the lesion is of paramount importance to achieve a successful outcome. Mosaicplasty is a viable option with which to address osteochondral lesions of the knee and offers the advantage of transplanting hyaline cartilage. However, limited graft availability and donor site morbidity are concerns. Transplantation of an osteochondral allograft consisting of intact, viable articular cartilage and its underlying subchondral bone offers the ability to address large osteochondral defects of the knee, including those involving an entire compartment. The primary theoretical advantage of autologous chondrocyte implantation is the development of hyaline-like cartilage rather than fibrocartilage in the defect, which presumably leads to better long-term outcomes and longevity of the healing tissue. Use of synthetic scaffolds is a potentially attractive alternative to traditional cartilage procedures as they are readily available and, unlike allogeneic tissue transplants, are associated with no risk of disease transmission. Their efficacy, however, has not been proven clinically. PMID: 20360528 [PubMed - indexed for MEDLINE]
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Related Articles Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. 2010 Jun;38(6):1110-6 Authors: Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH Abstract BACKGROUND: First-generation autologous chondrocyte implantation has limitations, and introducing new effective cell sources can improve cartilage repair. PURPOSE: This study was conducted to compare the clinical outcomes of patients treated with first-generation autologous chondrocyte implantation to patients treated with autologous bone marrow-derived mesenchymal stem cells (BMSCs). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Seventy-two matched (lesion site and age) patients underwent cartilage repair using chondrocytes (n = 36) or BMSCs (n = 36). Clinical outcomes were measured before operation and 3, 6, 9, 12, 18, and 24 months after operation using the International Cartilage Repair Society (ICRS) Cartilage Injury Evaluation Package, which included questions from the Short-Form Health Survey, International Knee Documentation Committee (IKDC) subjective knee evaluation form, Lysholm knee scale, and Tegner activity level scale. RESULTS: There was significant improvement in the patients' quality of life (physical and mental components of the Short Form-36 questionnaire included in the ICRS package) after cartilage repair in both groups (autologous chondrocyte implantation and BMSCs). However, there was no difference between the BMSC and the autologous chondrocyte implantation group in terms of clinical outcomes except for Physical Role Functioning, with a greater improvement over time in the BMSC group (P = .044 for interaction effect). The IKDC subjective knee evaluation (P = .861), Lysholm (P = .627), and Tegner (P = .200) scores did not show any significant difference between groups over time. However, in general, men showed significantly better improvements than women. Patients younger than 45 years of age scored significantly better than patients older than 45 years in the autologous chondrocyte implantation group, but age did not make a difference in outcomes in the BMSC group. CONCLUSION: Using BMSCs in cartilage repair is as effective as chondrocytes for articular cartilage repair. In addition, it required 1 less knee surgery, reduced costs, and minimized donor-site morbidity. PMID: 20392971 [PubMed - indexed for MEDLINE]
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Related Articles Functional tissue engineering of ligament healing. Sports Med Arthrosc Rehabil Ther Technol. 2010;2:12 Authors: Hsu SL, Liang R, Woo SL Abstract Ligaments and tendons are dense connective tissues that are important in transmitting forces and facilitate joint articulation in the musculoskeletal system. Their injury frequency is high especially for those that are functional important, like the anterior cruciate ligament (ACL) and medial collateral ligament (MCL) of the knee as well as the glenohumeral ligaments and the rotator cuff tendons of the shoulder. Because the healing responses are different in these ligaments and tendons after injury, the consequences and treatments are tissue- and site-specific. In this review, we will elaborate on the injuries of the knee ligaments as well as using functional tissue engineering (FTE) approaches to improve their healing. Specifically, the ACL of knee has limited capability to heal, and results of non-surgical management of its midsubstance rupture have been poor. Consequently, surgical reconstruction of the ACL is regularly performed to gain knee stability. However, the long-term results are not satisfactory besides the numerous complications accompanied with the surgeries. With the rapid development of FTE, there is a renewed interest in revisiting ACL healing. Approaches such as using growth factors, stem cells and scaffolds have been widely investigated. In this article, the biology of normal and healing ligaments is first reviewed, followed by a discussion on the issues related to the treatment of ACL injuries. Afterwards, current promising FTE methods are presented for the treatment of ligament injuries, including the use of growth factors, gene delivery, and cell therapy with a particular emphasis on the use of ECM bioscaffolds. The challenging areas are listed in the future direction that suggests where collection of energy could be placed in order to restore the injured ligaments and tendons structurally and functionally. PMID: 20492676 [PubMed]
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Related Articles New strategies for anterior cruciate ligament partial rupture using bone marrow transplantation in rats. Stem Cells Dev. 2011 Apr;20(4):671-9 Authors: Oe K, Kushida T, Okamoto N, Umeda M, Nakamura T, Ikehara S, Iida H Abstract The purpose of this study was to compare anterior cruciate ligament (ACL) regeneration between animal groups subjected to intra-articular injection of fresh whole bone marrow cells (BMCs), cultured mesenchymal stem cells (MSCs), or saline. Partially transected ACLs in Fischer 344/Nslc rats were prepared, followed by injection of BMCs, MSCs, or saline into the articular cavity at 1 week after transection. Donor cells expressing green fluorescent protein were detected in the recipient's transected ACLs at 4 weeks in the BMC and MSC groups, and their ACLs appeared almost normal histologically. Further, there were significantly more mature spindle cells in the BMC group than in the saline group at 4 weeks. Biomechanically, the tensile strength in the BMC group reached near normal levels at 4 weeks after injection. The levels of transforming growth factor-β1 in the ACL tissue and knee joint fluid in the BMC group were increased significantly compared with that of the saline group at 4 weeks as detected by immunohistochemical analysis. In conclusion, intra-articular bone marrow transplantation using fresh whole BMCs is an effective treatment for ACL partial rupture. This therapy is easy to apply in a clinical setting because no culture system is required for collecting MSCs. PMID: 20809695 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv Drug Deliv Rev. 2010 Sep 30;62(12):1167-74 Authors: Meyerrose T, Olson S, Pontow S, Kalomoiris S, Jung Y, Annett G, Bauer G, Nolta JA Abstract Mesenchymal stem cells (MSC) are a promising tool for cell therapy, either through direct contribution to the repair of bone, tendon and cartilage or as an adjunct therapy through protein production and immune mediation. They are an attractive vehicle for cellular therapies due to a variety of cell intrinsic and environmentally responsive properties. Following transplantation, MSC are capable of systemic migration, are not prone to tumor formation, and appear to tolerize the immune response across donor mismatch. These attributes combine to allow MSC to reside in many different tissue types without disrupting the local microenvironment and, in some cases, responding to the local environment with appropriate protein secretion. We describe work done by our group and others in using human MSC for the sustained in vivo production of supraphysiological levels of cytokines for the support of cotransplanted hematopoietic stem cells and enzymes that are deficient in animal models of lysosomal storage disorders such as MPSVII. In addition, the use of MSC engineered to secrete protein products has been reviewed in several fields of tissue injury repair, including but not limited to revascularization after myocardial infarction, regeneration of intervertebral disc defects and spine therapy, repair of stroke, therapy for epilepsy, skeletal tissue repair, chondrogenesis/knee and joint repair, and neurodegenerative diseases. Genetically engineered MSC have thus proven safe and efficacious in numerous animal models of disease modification and tissue repair and are poised to be tested in human clinical trials. The potential for these interesting cells to secrete endogenous or transgene products in a sustained and long-term manner is highly promising and is discussed in the current review. PMID: 20920540 [PubMed - indexed for MEDLINE]
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Related Articles Treatment of chondral defects of the knee with one step matrix-assisted technique enhanced by autologous concentrated bone marrow: in vitro characterisation of mesenchymal stem cells from iliac crest and subchondral bone. Injury. 2010 Nov;41(11):1172-7 Authors: de Girolamo L, Bertolini G, Cervellin M, Sozzi G, Volpi P Abstract Cartilage repair is still an unsolved problem. In the last years many cell-based treatments have been proposed, in order to obtain good regeneration of cartilage defects. The Autologous Matrix-Induced Chondrogenesis technique (AMIC(®)) combines the micro-fracture procedure with the use of a specific biological membrane. The phenotypic feature of bone marrow cell population, harvested from iliac crest and knee subchondral bone of patients treated with the AMIC(®) technique, enhanced by autologous concentrated bone marrow, was analysed to evaluate potential variations of the cell population. Samples of eleven patients, with isolated chondral lesions grade III or IV were treated with the AMIC(®) technique, enhanced by the use of autologous concentrated bone marrow. A small fraction of bone marrow samples, both from iliac crest and from the created micro-fractures, was analysed by FACS analysis and then cultured to verify their proliferative and differentiation potential. An average of 0.04% of concentrated bone marrow cells harvested from the iliac crest, presented mesenchymal stem cell phenotype (CD34(-)/CD45(low)/CD271(high)), whereas just 0.02% of these cells were identified from the samples harvested during the creation of micro-fractures at the knee. After two passages in culture, cells expressed a peculiar profile for MSC. Only MSC from bone marrow could be long-term propagated and were able to efficiently differentiate in the cultures. Although the AMIC(®) approach has many advantages, the surgical technique in the application of the microfracture technique remains essential and affects the final result. PMID: 20934693 [PubMed - indexed for MEDLINE]
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Related Articles Enhancement of rotator cuff tendon-bone healing with injectable periosteum progenitor cells-BMP-2 hydrogel in vivo. Knee Surg Sports Traumatol Arthrosc. 2011 Sep;19(9):1597-607 Authors: Chen CH, Chang CH, Wang KC, Su CI, Liu HT, Yu CM, Wong CB, Wang IC, Whu SW, Liu HW Abstract PURPOSE: The fixation and incorporation of ruptured rotator cuff tendon to bone is a major concern in rotator cuff repair surgery. Rotator cuff repair usually fails at the tendon-bone interface, especially in case of large or massive tears. To enhance tendon-bone healing, an injectable hydrogel made with periosteal progenitor cells(PPCs) and poly (ethylene glycol) diacrylate (PEGDA) tethered with bone morphogenic protein-2(BMP-2) was developed to encourage extracellular matrix synthesis for tendon-to-bone healing in rotator cuff repair. METHODS: The infraspinatus tendon was cut from the greater tuberosity and repaired through a transosseous tunnel with the injectable progenitor cell-BMP-2 hydrogel applied between the tendon-bone interface. The injectable hydrogel was prepared from 10% poly (ethylene glycol) diacrylate (PEGDA) containing 0.05% of the photoinitiator. BMP-2 tethered with poly(ethylene glycol) (PEG) was blended to the hydrogel. Rabbit periosteal progenitor cells (PPCs) isolated from periosteum were mixed with hydrogel and injected on the tendon-bone interface. Ultraviolet radiation (365 nm) was applied for 60 s to photopolymerize the injection and solidify the hydrogel. The rabbits were killed at 4 and 8 weeks. The morphological characteristics of the healing tendon-to-bone interface were evaluated by histological and immunohistochemical methods. The biomechanical test was done to determine healing attachment strength. RESULTS: At both the 4- and 8-week killing, histological analysis of the tendon-bone interface showed an increasing fibrocartilage and bone layer formed in the tendon-bone interface in PEGDA group. At 4 weeks, fibrocartilage-like tissue was observed in a focal area. At 8 weeks, further matrix deposition occurred with fibrocartilage formation in the tendon-bone junction, and bone formation appeared near host bone. Immunohistochemistry revealed the presence of aggrecan and type II collagen. Biomechanical testing revealed a higher maximum pull-out load at all time points with a statistically significant difference at 4 and 8 weeks postoperatively. CONCLUSION: PEGDA hydrogel was approved as an adequate matrix for the encapsulation of cells and signal factor, and as an effective local delivery method to the tendon-bone interface through injection and photopolymerization. The PPCs-BMP2-hydrogel provides a powerful inductive ability between the tendon and the bone and enhances tendon-bone healing through the neoformation of fibrocartilage. PMID: 21327764 [PubMed - indexed for MEDLINE]
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Related Articles Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: a report of 5 cases with histology. Arthroscopy. 2011 Apr;27(4):493-506 Authors: Saw KY, Anz A, Merican S, Tay YG, Ragavanaidu K, Jee CS, McGuire DA Abstract PURPOSE: The purpose of this study was to evaluate the quality of articular cartilage regeneration after arthroscopic subchondral drilling followed by postoperative intraarticular injections of autologous peripheral blood progenitor cells (PBPCs) in combination with hyaluronic acid (HA). METHODS: Five patients underwent second-look arthroscopy with chondral core biopsy. These 5 patients are part of a larger pilot study in which 180 patients with International Cartilage Repair Society grade III and IV lesions of the knee joint underwent arthroscopic subchondral drilling followed by postoperative intra-articular injections. Continuous passive motion was used on the operated knee 2 hours per day for 4 weeks. Partial weight bearing was observed for the first 6 to 8 weeks. Autologous PBPCs were harvested 1 week after surgery. One week after surgery, 8 mL of the harvested PBPCs in combination with 2 mL of HA was injected intra-articularly into the operated knee. The remaining PBPCs were divided into vials and cryopreserved. A total of 5 weekly intra-articular injections were given. RESULTS: Second-look arthroscopy confirmed articular cartilage regeneration, and histologic sections showed features of hyaline cartilage. Apart from the minimal discomfort of PBPC harvesting and localized pain associated with the intra-articular injections, there were no other notable adverse reactions. CONCLUSIONS: Articular hyaline cartilage regeneration is possible with arthroscopic subchondral drilling followed by postoperative intraarticular injections of autologous PBPCs in combination with HA. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID: 21334844 [PubMed - indexed for MEDLINE]
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Related Articles Articular cartilage repair using an intra-articular magnet and synovium-derived cells. J Orthop Res. 2011 Apr;29(4):531-8 Authors: Hori J, Deie M, Kobayashi T, Yasunaga Y, Kawamata S, Ochi M Abstract The purpose of this study was to investigate the chondrogenic potential of magnetically labeled synovium-derived cells (M-SDCs) and examine whether M-SDCs could repair the articular cartilage using an intra-articular magnet after delivery to the lesion. Synovium-derived cells (SDCs) were cultured from the synovium of a rat knee, and were magnetically labeled with ferumoxides. M-SDCs were examined with a transmission electron microscope. A pellet culture system was used to evaluate the chondrogenic potential of M-SDCs in a magnetic field. In a rat model, allogeneic M-SDCs were injected into the knee after we made an osteochondral defect on the patellar groove and implanted an intra-articular magnet at the bottom of the defect. We histologically examined the defects at 48 h, 4 weeks, 8 weeks, and 12 weeks after treatment. Electron microscopy showed the transfection of ferumoxides into SDCs. The pellet cultures revealed the chondrogenic potential of M-SDCs in a magnetic field. M-SDCs accumulated in the osteochondral defect at 48 h after treatment, and we confirmed the regeneration of the articular cartilage at 4 weeks, 8 weeks, and 12 weeks after treatment using an intra-articular magnet. We demonstrated that articular cartilage defects could be repaired using an intra-articular magnet and M-SDCs. We believe that this system will be useful to repair human articular cartilage defects. PMID: 21337393 [PubMed - indexed for MEDLINE]
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Related Articles [The treatment of focal chondral lesions of the knee]. Harefuah. 2010 Aug;149(8):542-6, 549 Authors: Khashan M, Chechik O, Arbel R, Morag G Abstract Focal osteochondral lesions of the knee are a common cause of pain and other knee symptoms, and are mostly caused by traumatic injuries. The spontaneous repair ability of the articular cartilage tissue is very limited. Thus, focal chondral lesions result in early degenerative changes and post-traumatic osteoarthritis. The surgical treatment of focal osteochondral lesions can be divided into three major groups: cartilage debridement techniques, marrow stimulating techniques and transplantation techniques. Lesion debridement causes limited and temporary symptoms relief. While marrow stimulating techniques are considered simple, cheap and easy to perform, some of the transplantation techniques are complicated and consist of highly demanding surgery and new technologies of tissue engineering. Many published studies attempted to evaluate the efficacy of the treatment methods and to compare between them. There is no obvious or definite advantage of any one technique. There are relative advantages of some techniques according to the lesion size and patient's factors. Yet, among the current available treatment options none was found to produce hyaline cartilage consistently. In order to improve the current treatment and to find new treatment techniques, significant advances were achieved in the research of stem cells, scaffolds and growth factors in the last years. Further advances and more comparative and long term studies, particularly those that evaluate the efficacy of the new treatment techniques are needed. PMID: 21341437 [PubMed - indexed for MEDLINE]
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Related Articles Prevention and management of knee osteoarthritis and knee cartilage injury in sports. Br J Sports Med. 2011 Apr;45(4):304-9 Authors: Takeda H, Nakagawa T, Nakamura K, Engebretsen L Abstract Articular cartilage defects in the knee of young or active individuals remain a problem in orthopaedic practice. These defects have limited ability to heal and may progress to osteoarthritis. The prevalence of knee osteoarthritis among athletes is higher than in the non-athletic population. The clinical symptoms of osteoarthritis are joint pain, limitation of range of motion and joint stiffness. The diagnosis of osteoarthritis is confirmed by the symptoms and the radiological findings (narrowing joint space, osteophyte formation and subchondral sclerosis). There is no strong correlation between symptoms and radiographic findings. The aetiology of knee osteoarthritis is multifactorial. Excessive musculoskeletal loading (at work or in sports), high body mass index, previous knee injury, female gender and muscle weakness are well-known risk factors. The high-level athlete with a major knee injury has a high incidence of knee osteoarthritis. Cartilage injuries are frequently observed in young and middle-aged active athletes. Often this injury precedes osteoarthritis. Reducing risk factors can decrease the prevalence of knee osteoarthritis. The prevention of knee injury, especially anterior cruciate ligament and meniscus injury in sports, is important to avoid progression of knee osteoarthritis. PMID: 21357577 [PubMed - indexed for MEDLINE]
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Related Articles A preliminary study comparing the use of allogenic chondrogenic pre-differentiated and undifferentiated mesenchymal stem cells for the repair of full thickness articular cartilage defects in rabbits. J Orthop Res. 2011 Sep;29(9):1336-42 Authors: Dashtdar H, Rothan HA, Tay T, Ahmad RE, Ali R, Tay LX, Chong PP, Kamarul T Abstract Chondrogenic differentiated mesenchymal stem cells (CMSCs) have been shown to produce superior chondrogenic expression markers in vitro. However, the use of these cells in vivo has not been fully explored. In this study, in vivo assessment of cartilage repair potential between allogenic-derived chondrogenic pre-differentiated mesenchymal stem cells and undifferentiated MSCs (MSCs) were compared. Bilateral full thickness cartilage defects were created on the medial femoral condyles of 12 rabbits (n = 12). Rabbits were divided into two groups. In one group, the defects in the right knees were repaired using alginate encapsulated MSCs while in the second group, CMSCs were used. The animals were sacrificed and the repaired and control knees were assessed at 3 and 6 months after implantation. Quantitative analysis was performed by measuring the Glycosaminoglycans (GAGs)/total protein content. The mean Brittberg score was higher in the transplanted knees as compared to the untreated knee at 6 months (p < 0.05). Quantitative analysis of GAGs was consistent with these results. Histological and immunohistochemical analysis demonstrated hyaline-like cartilage regeneration in the transplanted sites. Significant differences between the histological scores based on O'Driscoll histological grading were observed between contralateral knees at both 3 and 6 months (p < 0.05). No significant differences were observed between the Britberg, O'Driscoll scores, and GAGs/total protein content when comparing defect sites treated with MSC and CMSC (p > 0.05). This study demonstrates that the use of either MSC or CMSC produced superior healing when compared to cartilage defects that were untreated. However, both cells produced comparable treatment outcomes. PMID: 21445989 [PubMed - indexed for MEDLINE]
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Related Articles In vitro targeted magnetic delivery and tracking of superparamagnetic iron oxide particles labeled stem cells for articular cartilage defect repair. J Huazhong Univ Sci Technolog Med Sci. 2011 Apr;31(2):204-9 Authors: Feng Y, Jin X, Dai G, Liu J, Chen J, Yang L Abstract To assess a novel cell manipulation technique of tissue engineering with respect to its ability to augment superparamagnetic iron oxide particles (SPIO) labeled mesenchymal stem cells (MSCs) density at a localized cartilage defect site in an in vitro phantom by applying magnetic force. Meanwhile, non-invasive imaging techniques were use to track SPIO-labeled MSCs by magnetic resonance imaging (MRI). Human bone marrow MSCs were cultured and labeled with SPIO. Fresh degenerated human osteochondral fragments were obtained during total knee arthroplasty and a cartilage defect was created at the center. Then, the osteochondral fragments were attached to the sidewalls of culture flasks filled with phosphate-buffered saline (PBS) to mimic the human joint cavity. The SPIO-labeled MSCs were injected into the culture flasks in the presence of a 0.57 Tesla (T) magnetic force. Before and 90 min after cell targeting, the specimens underwent T2-weighted turbo spin-echo (SET2WI) sequence of 3.0 T MRI. MRI results were compared with histological findings. Macroscopic observation showed that SPIO-labeled MSCs were steered to the target region of cartilage defect. MRI revealed significant changes in signal intensity (P<0.01). HE staining exibited that a great number of MSCs formed a three-dimensional (3D) cell "sheet" structure at the chondral defect site. It was concluded that 0.57 T magnetic force permits spatial delivery of magnetically labeled MSCs to the target region in vitro. High-field MRI can serve as an very sensitive non-invasive technique for the visualization of SPIO-labeled MSCs. PMID: 21505986 [PubMed - indexed for MEDLINE]
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Related Articles In vivo evaluation of gene transfer into mesenchymal cells (in view of cartilage repair). Methods Mol Biol. 2011;737:391-405 Authors: Gelse K, Schneider H Abstract Gene transfer of specific growth factors is suitable for inducing chondrogenic differentiation of -mesenchymal cells to be used for cartilage regeneration. However, extent and quality of repair tissue formation also depend on biomechanical and metabolic influences that can only be studied in vivo. We describe three methods to evaluate viral gene transfer into mesenchymal cells in animal models of articular cartilage defects, e.g., mouse, rat and miniature pig models, focussing on the repair of hyaline cartilage tissue. PMID: 21590406 [PubMed - indexed for MEDLINE]
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Related Articles Patellar chondral defects: a review of a challenging entity. Knee Surg Sports Traumatol Arthrosc. 2011 Dec;19(12):1990-2001 Authors: Mouzopoulos G, Borbon C, Siebold R Abstract PURPOSE: The aim of this study was to perform a review of the management of patellar cartilage defects, identify prognostic factors for better clinical outcomes, and propose a treatment algorithm of this challenging entity. METHODS: We conducted a review of multiple databases, evaluating the clinical outcomes after patellar cartilage lesion treatment. Because of the heterogeneity of data, a meta-analysis could not be performed. RESULTS: Twelve studies were identified for inclusion. Based on the clinical outcomes of these studies, a treatment algorithm was proposed. The clinical outcomes after patellar cartilage defects repair depend on the location and size of the articular defect, the age of the patient, the successful reconstruction of the patellar ridge, the repair of extensor mechanism malalignment, and the coexistence of chondromalacia. CONCLUSION: The optimal treatment for cartilaginous defects of the patella is still elusive. More prospective studies are needed, in order to identify which techniques are cost-effective especially on a long-term basis. PMID: 21607740 [PubMed - indexed for MEDLINE]
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Related Articles Differential properties of human ACL and MCL stem cells may be responsible for their differential healing capacity. BMC Med. 2011;9:68 Authors: Zhang J, Pan T, Im HJ, Fu FH, Wang JH Abstract BACKGROUND: The human anterior cruciate ligament (hACL) and medial collateral ligament (hMCL) of the knee joint are frequently injured, especially in athletic settings. It has been known that, while injuries to the MCL typically heal with conservative treatment, ACL injuries usually do not heal. As adult stem cells repair injured tissues through proliferation and differentiation, we hypothesized that the hACL and hMCL contain stem cells exhibiting unique properties that could be responsible for the differential healing capacity of the two ligaments. METHODS: To test the above hypothesis, we derived ligament stem cells from normal hACL and hMCL samples from the same adult donors using tissue culture techniques and characterized their properties using immunocytochemistry, RT-PCR, and flow cytometry. RESULTS: We found that both hACL stem cells (hACL-SCs) and hMCL stem cells (hMCL-SCs) formed colonies in culture and expressed stem cell markers nucleostemin and stage-specific embryonic antigen-4 (SSEA-4). Moreover, both hACL-SCs and hMCL-SCs expressed CD surface markers for mesenchymal stem cells, including CD44 and CD90, but not those markers for vascular cells, CD31, CD34, CD45, and CD146. However, hACL-SCs differed from hMCL-SCs in that the size and number of hACL-SC colonies in culture were much smaller and grew more slowly than hMCL-SC colonies. Moreover, fewer hACL-SCs in cell colonies expressed stem cell markers STRO-1 and octamer-binding transcription factor-4 (Oct-4) than hMCL-SCs. Finally, hACL-SCs had less multi-differentiation potential than hMCL-SCs, evidenced by differing extents of adipogenesis, chondrogenesis, and osteogenesis in the respective induction media. CONCLUSIONS: This study shows for the first time that hACL-SCs are intrinsically different from hMCL-SCs. We suggest that the differences in their properties contribute to the known disparity in healing capabilities between the two ligaments. PMID: 21635735 [PubMed - indexed for MEDLINE]
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Related Articles Spatiotemporal control of proliferation and differentiation of bone marrow-derived mesenchymal stem cells recruited using collagen hydrogel for repair of articular cartilage defects. J Biomed Mater Res B Appl Biomater. 2011 Aug;98(2):360-8 Authors: Mimura T, Imai S, Okumura N, Li L, Nishizawa K, Araki S, Ueba H, Kubo M, Mori K, Matsusue Y Abstract Articular cartilage has a poor healing capacity, and cartilage regeneration is not always warranted to achieve healing. On the other hand, collagen scaffolds have been shown to support regeneration of articular cartilage defects in animal models, whereas bone morphogenetic protein-2 (BMP-2) is known to cause chondrogenic differentiation of marrow-derived mesenchymal stem cells (MSCs). The purpose of this study was to evaluate the effectiveness of intra-articular administration of BMP-2 into bone marrow-derived MSCs recruited to defects using original collagen hydrogel in rabbits at various time points. Full-thickness defects were created in both knees, then collagen hydrogels were transplanted, and BMP-2 was supplied for 1-week periods, as follows. BMP-2 was administered immediately after the operation for 1 week (BMP0-1 group), and BMP-2 was administered between weeks 1 and 2 after the operation (BMP1-2 group). BMP2 was administered between weeks 2 and 3 (BMP2-3 group). Specimens were then obtained, and bromodeoxyuridine (BrdU)-positive cells were enumerated and histologic grading was also performed. In addition, the gene expression analysis was performed using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) assays. Enumeration of BrdU-positive cells showed a significant increase in the BMP0-1 group compared with the other groups. Similarly, histologic scores in the BMP0-1 group were superior for up to 8 weeks. Finally, RT-PCR findings revealed that immediate BMP-2 administration enhanced chondrogenic differentiation. PMID: 21648062 [PubMed - indexed for MEDLINE]
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Related Articles Knee chondral injuries: clinical treatment strategies and experimental models. Injury. 2012 Jun;43(6):694-705 Authors: Vaquero J, Forriol F Abstract Articular cartilage has a very limited capacity to repair and as such premature joint degeneration is often the end point of articular injuries. Patients with chondral injury have asymptomatic periods followed by others in which discomfort or pain is bearable. The repair of focal cartilage injuries requires a precise diagnosis, a completed knee evaluation to give the correct indication for surgery proportional to the damage and adapted to each patient. Many of the surgical techniques currently performed involve biotechnology. The future of cartilage repair should be based on an accurate diagnosis using new MRI techniques. Clinical studies would allow us to establish the correct indications and surgical techniques implanting biocompatible and biodegradable matrices with or without stem cells and growth factors. Arthroscopic techniques with the design of new instruments can facilitate repair of patella and tibial plateau lesions. PMID: 21733516 [PubMed - indexed for MEDLINE]
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Related Articles Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells. Knee Surg Sports Traumatol Arthrosc. 2012 Feb;20(2):373-7 Authors: Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R Abstract PURPOSE: To investigate the behavior of rotator cuff tears treated with conventional repair technique with the aid of autologous bone marrow mononuclear cells (BMMC). METHODS: Fourteen consecutive patients (9 women, 5 men, mean age of 59.2 years) with complete rotator cuff tears (mean preoperative UCLA score of 12 ± 3.0) were fixed by transosseous stitches through mini-open incision, with subsequent injection of BMMC into the tendon borders, obtained from the iliac crest just prior to surgery. Magnetic resonance images (MRI) were acquired before and after surgery and evaluated by two musculoskeletal radiologists regarding new postoperative findings of patients treated with BMMC. RESULTS: After a minimum 12-month follow-up period, the UCLA score increased from 12 ± 3.0 to 31 ± 3.2. Clinical findings remained unaltered in the following year in all but one patient (13/14). MRI analysis after a 12-month follow-up period demonstrated tendon integrity in all cases (14/14), presence of low-signal intensity areas along the supraspinatus tendon and distal muscle belly in 8 cases (8/14), and high-intensity blooming small round artifact at the bursal and tendon topography in 11 cases (11/14). Six patients (6/14) showed formation of a high-signal intensity zone at the critical zone. Clinical findings remained unaltered in the following year in all but one patient, who relapsed into loss of strength and pain, being considered a bad result. CONCLUSION: Implantation of BMMC in rotator cuff sutures appears to be a safe and promising alternative to other biological approaches currently used to enhance tissue quality in affected tendons. PMID: 21773831 [PubMed - indexed for MEDLINE]
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Related Articles Infrapatellar fat pad may be with tendon repairing ability and closely related with the developing process of patella Baja. Med Hypotheses. 2011 Oct;77(4):620-3 Authors: Liu YP, Li SZ, Yuan F, Xia J, Yu X, Liu X, Yu GR Abstract Patella Baja, as a common complication of knee trauma or knee surgery, was very difficult to deal with, and scarring and shortening of the patellar tendon were looked on as the most important reason for it. Infrapatellar fat pad, also known as Hoffa's fat pad was traditionally regarded as with only buffering and lubricating functions in knee joints, which can limit the knee's excessive activities, absorb shocks from the anterior knee and reduces friction between the patellar tendon and the tibia, it should be with direct protection function and avoid the damage of patella tendon. Recently, a large number of studies had shown that adipose tissue was an accessible and abundant source of mesenchymal stem cells for tissue engineering. Adipose derived stem cells (ADSCs) can be induced to differentiate into adipocytes, osteoblasts, nerve cells, tendon cells and so on. In addition, interestingly, infrapatellar fat pad were just located behind the patellar tendon, and SDF-1 (stromal cell-derived factor-1), as a powerful cytokine that regulates inflammatory cell recruitment and stem cell homing, was unregulated after ligament injury, so there may be a certain correlation between ADSCs from infrapatellar fat pad and injured tendons, maybe ADSCs from infrapatellar fat pad can biologically repair injured tendons when patella tendon was damaged. We hypothesized injured patella tendon repairing should include not only the self-repairing of the tendon, but also the biological repairing from ADSCs in infrapatellar fat pad. When both of the repairing failed to repair the damage of the tendon, patellar tendon may begin to shrink and scar, which will result in patella Baja. In our opinion, healthy infrapatellar fat pad was with direct protection function of patella tendon and full of rich ADSCs, which may play an important part in patella tendon repairing and the developing process of patella Baja. PMID: 21821366 [PubMed - indexed for MEDLINE]
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Related Articles Advances in meniscal tissue engineering. Ortop Traumatol Rehabil. 2011 Jul-Aug;13(4):319-26 Authors: Eli N, Oragui E, Khan W Abstract Injuries and lesions to the meniscal cartilage of the knee joint are common. As a result of its limited regenerative capacity, early degenerative changes to the articular surface frequently occur, resulting in pain and poor function. Currently available surgical interventions include repair of tears, and partial and total meniscectomy but the results are inconsistent and often poor. Interest in the field of meniscal tissue engineering with the possibilities of better treatment outcomes has grown in recent times. Current research has focused on the use of mesenchymal stem cells, fibrochondrocytes, meniscal derived cells and fibroblast-like synoviocytes in tissue engineering. Mesenchymal stem cells are multipotent cells that have been identified in a number of tissues including bone marrow and synovium. Current research is aimed at defining the correct combination of cytokines and growth factors necessary to induce specific tissue formation and includes transforming growth factor-β (TGF-β), Platelet Derived Growth Factor (PDGF) and Fibroblast Growth Factor 2 (FGF2). Scaffolds provide mechanical stability and integrity, and supply a template for three-dimensional organization of the developing tissue. A number of experimental and animal models have been used to investigate the ideal scaffolds for meniscal tissue engineering. The ideal scaffold for meniscal tissue engineering has not been identified but biodegradable scaffolds have shown the most promising results. In addition to poly-glycolic acid (PGA) and poly-lactic acid (PLLA) scaffolds, new synthetic hydrogels and collagen sponges are also being explored. There are two synthetic meniscal implants currently in clinical use and there are a number of clinical trials in the literature with good short- and medium-term results. Both products are indicated for segmental tissue loss and not for complete meniscal replacement. The long-term results of these implants are unknown and we wait to see whether they will be proved to have benefits in delaying arthritic change and chondral damage. PMID: 21857063 [PubMed - indexed for MEDLINE]
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Related Articles Evaluation of intra-articular mesenchymal stem cells to augment healing of microfractured chondral defects. Arthroscopy. 2011 Nov;27(11):1552-61 Authors: McIlwraith CW, Frisbie DD, Rodkey WG, Kisiday JD, Werpy NM, Kawcak CE, Steadman JR Abstract PURPOSE: This study evaluated intra-articular injection of bone marrow-derived mesenchymal stem cells (BMSCs) to augment healing with microfracture compared with microfracture alone. METHODS: Ten horses (aged 2.5 to 5 years) had 1-cm2 defects arthroscopically created on both medial femoral condyles of the stifle joint (analogous to the human knee). Defects were debrided to subchondral bone followed by microfracture. One month later, 1 randomly selected medial femorotibial joint in each horse received an intra-articular injection of either 20 × 10(6) BMSCs with 22 mg of hyaluronan or 22 mg of hyaluronan alone. Horses were confined for 4 months, with hand walking commencing at 2 weeks and then increasing in duration and intensity. At 4 months, horses were subjected to strenuous treadmill exercise simulating race training until completion of the study at 12 months. Horses underwent musculoskeletal and radiographic examinations bimonthly and second-look arthroscopy at 6 months. Horses were euthanized 12 months after the defects were made, and the affected joints underwent magnetic resonance imaging and gross, histologic, histomorphometric, immunohistochemical, and biochemical examinations. RESULTS: Although there was no evidence of any clinically significant improvement in the joints injected with BMSCs, arthroscopic and gross evaluation confirmed a significant increase in repair tissue firmness and a trend for better overall repair tissue quality (cumulative score of all arthroscopic and gross grading criteria) in BMSC-treated joints. Immunohistochemical analysis showed significantly greater levels of aggrecan in repair tissue treated with BMSC injection. There were no other significant treatment effects. CONCLUSIONS: Although there was no significant difference clinically or histologically in the 2 groups, this study confirms that intra-articular BMSCs enhance cartilage repair quality with increased aggrecan content and tissue firmness. CLINICAL RELEVANCE: Clinical use of BMSCs in conjunction with microfracture of cartilage defects may be potentially beneficial. PMID: 21862278 [PubMed - indexed for MEDLINE]
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Related Articles A mathematical model of cartilage regeneration after cell therapy. J Theor Biol. 2011 Nov 21;289:136-50 Authors: Lutianov M, Naire S, Roberts S, Kuiper JH Abstract Autologous Chondrocyte Implantation (ACI) is a cell-based therapy used mainly for the treatment of chondral defects in the knee. It involves surgically inserting isolated chondrocytes or mesenchymal stem cells (MSCs), previously expanded in culture, into the defect region. These chondrocytes then proliferate and migrate in the process forming extracellular matrix (ECM) and new cartilage. In the case of MSCs, the process of forming new cartilage is initiated only after differentiation of the stem cells into chondrocytes. Many details of the repair process following insertion in humans are unknown. To enable better understanding of the repair process, we present a mathematical model of cartilage regeneration after cell therapy. The key mechanisms involved in the regeneration process are simulated by modelling cell migration, proliferation and differentiation, nutrient diffusion and depletion, and ECM synthesis and degradation at the defect site, both spatially and temporally. The model successfully simulates the progression of cartilage regeneration. The model predicts a time frame of about 18months for the defect to reach full maturation which corresponds with results from clinical studies and demonstrates that cartilage regeneration is a slow process. Moreover, the model also suggests that regeneration using stem cells alone is no better than that using chondrocytes. The stem cells need to first differentiate into chondrocytes before forming ECM and new cartilage, a process that is initiated only after the stem cell density exceeds a threshold value. Furthermore, with chondrocytes alone, the matrix seems to develop from the subchondral bone interface as compared to the normal cartilage interface, in the case of stem cells alone. The influence of initial conditions and parameters, such as the initial cell seeding densities and cell proliferation rates, is shown to not significantly influence the general evolution characteristics other than accelerating the initial growth process. The model presented here is a first approach towards better understanding of cartilage regeneration after cell therapy techniques. PMID: 21871899 [PubMed - indexed for MEDLINE]
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Related Articles All-arthroscopic AMIC procedure for repair of cartilage defects of the knee. Knee Surg Sports Traumatol Arthrosc. 2012 May;20(5):922-5 Authors: Piontek T, Ciemniewska-Gorzela K, Szulc A, Naczk J, Słomczykowski M Abstract PURPOSE: Bone marrow mesenchymal stem cells were introduced into clinical practice due to their ability to differentiate into many types of cells. Autologous matrix-induced chondrogenesis (AMIC) combines the microfracture method with matrix-based techniques that utilizes a collagen membrane to serve as a scaffold for new bone marrow mesenchymal stem cells, allowing effective reconstruction of even large fragments of a damaged cartilage surface. METHODS: All-arthroscopic technique to repair knee cartilage defects using the AMIC technique, which includes the use of a collagen matrix (porcine collagen type I and III) and fibrin glue-technique presentation. CONCLUSION: This technical note introduces an all-arthroscopic AMIC technique to reconstruct extensive cartilage defects (without bone defects). The technique may be used for treatment of all location of knee cartilage lesions. LEVEL OF EVIDENCE: V. PMID: 21910000 [PubMed - indexed for MEDLINE]
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Related Articles Osteochondral tissue engineering approaches for articular cartilage and subchondral bone regeneration. Knee Surg Sports Traumatol Arthrosc. 2012 Jun;20(6):1182-91 Authors: Panseri S, Russo A, Cunha C, Bondi A, Di Martino A, Patella S, Kon E Abstract PURPOSE: Osteochondral defects (i.e., defects which affect both the articular cartilage and underlying subchondral bone) are often associated with mechanical instability of the joint and therefore with the risk of inducing osteoarthritic degenerative changes. This review addresses the current surgical treatments and most promising tissue engineering approaches for articular cartilage and subchondral bone regeneration. METHODS: The capability to repair osteochondral or bone defects remains a challenging goal for surgeons and researchers. So far, most clinical approaches have been shown to have limited capacity to treat severe lesions. Current surgical repair strategies vary according to the nature and size of the lesion and the preference of the operating surgeon. Tissue engineering has emerged as a promising alternative strategy that essentially develops viable substitutes capable of repairing or regenerating the functions of damaged tissue. RESULTS: An overview of novel and most promising osteochondroconductive scaffolds, osteochondroinductive signals, osteochondrogenic precursor cells, and scaffold fixation approaches are presented addressing advantages, drawbacks, and future prospectives for osteochondral regenerative medicine. CONCLUSION: Tissue engineering has emerged as an excellent approach for the repair and regeneration of damaged tissue, with the potential to circumvent all the limitations of autologous and allogeneic tissue repair. LEVEL OF EVIDENCE: Systematic review, Level III. PMID: 21910001 [PubMed - indexed for MEDLINE]
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Related Articles Role of angiogenesis after muscle derived stem cell transplantation in injured medial collateral ligament. J Orthop Res. 2012 Apr;30(4):627-33 Authors: Nishimori M, Matsumoto T, Ota S, Kopf S, Mifune Y, Harner C, Ochi M, Fu FH, Huard J Abstract We performed this study to investigate the therapeutic role of vascular endothelial growth factor (VEGF) in medial collateral ligament (MCL) healing. Murine muscle derived stem cells (MDSCs) obtained via the preplate technique were retrovirally transduced to express: (1) VEGF and nLacZ (MDSC-VEGF), (2) soluble fms-like tyrosine kinase-1 (sFLT1, a VEGF-specific antagonist) and nLacZ (MDSC-sFLT1), and (3) nLacZ (MDSC-nLacZ). After transecting the MCL of immunodeficient rats, 5 × 10(5)  cells of each of the transduction groups list above were transplanted into the MCL injury site. A control group was injected with phosphate-buffered saline (PBS) only. Immunohistochemical staining demonstrated that there were more Isolectin B4 and β-galactosidase double positive cells in the rats transplanted with MDSC-VEGF transduced cells than the other groups at week 1. Capillary density was significantly higher in the MDSC-VEGF group than the other groups at week 2; however, there were no significant differences in the biomechanical assessment between the MDSC-VEGF and MDSC-nLacZ groups. On the other hand, the MDSC-sFLT1 group revealed a lower capillary density than the other two groups and the functional ligament healing of the MDSC-sFLT1 group was significantly decreased compared to the other groups when assessed biomechanically. The findings of the present study suggest that angiogenesis plays a critical role in the healing process of injured MCL. PMID: 21913220 [PubMed - indexed for MEDLINE]
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Related Articles Treatment outcomes of alginate-embedded allogenic mesenchymal stem cells versus autologous chondrocytes for the repair of focal articular cartilage defects in a rabbit model. Am J Sports Med. 2012 Jan;40(1):83-90 Authors: Tay LX, Ahmad RE, Dashtdar H, Tay KW, Masjuddin T, Ab-Rahim S, Chong PP, Selvaratnam L, Kamarul T Abstract BACKGROUND: Mesenchymal stem cells (MSCs) represent a promising alternative form of cell-based therapy for cartilage injury. However, the capacity of MSCs for chondrogenesis has not been fully explored. In particular, there is presently a lack of studies comparing the effectiveness of MSCs to conventional autologous chondrocyte (autoC) treatment for regeneration of full-thickness cartilage defects in vivo. HYPOTHESIS: Treatment with allogenic undifferentiated MSCs (alloMSCs) results in superior cartilage tissue regeneration profiles when compared with autoC for repair of focal articular cartilage defects. STUDY DESIGN: Controlled laboratory study. METHODS: Full-thickness articular cartilage defects were created on the weightbearing surface of the medial femoral condyles in both knees of New Zealand White rabbits (N = 30). Six weeks after the defect was induced, the right knee was treated with either alloMSCs (n = 12) or autoC (n = 18), while the left knee remained untreated (control). The rabbits were sacrificed at 6 months after treatment for assessment of cartilage tissue regeneration, which included the Brittberg morphologic score, histologic grading by O'Driscoll score, and quantitative analysis of glycosaminoglycans per total protein content. RESULTS: Apart from significantly higher Brittberg scores in the alloMSC treatment group (8.8 ± 0.8) versus the autoC treatment group (6.6 ± 0.8) (P = .04), both treatments showed similar cartilage regenerative profiles. All outcome measures were significantly higher in the treatment groups compared with their respective controls (P < .05). CONCLUSION: AlloMSCs have similar effectiveness as autoC for repair of focal cartilage defects. Both treatments resulted in superior tissue regeneration compared with untreated defects. CLINICAL RELEVANCE: The results have an implication of supporting the potential use of MSCs for cartilage repair after sports injuries or diseases, in view of similar efficacy but less patient morbidity and potential cost savings as compared with conventional autoC therapy. PMID: 21917609 [PubMed - indexed for MEDLINE]
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Related Articles Rapid isolation of human stem cells (connective progenitor cells) from the distal femur during arthroscopic knee surgery. Arthroscopy. 2012 Jan;28(1):74-84 Authors: Beitzel K, McCarthy MB, Cote MP, Chowaniec D, Falcone LM, Falcone JA, Dugdale EM, Deberardino TM, Arciero RA, Mazzocca AD Abstract PURPOSE: (1) To safely obtain bone marrow aspirates from the distal femur during arthroscopic knee surgery, (2) to purify and efficiently concentrate connective tissue progenitor cells (CTPs) in the operating room (OR), and (3) to confirm that these are CTPs through their ability to differentiate into bone cells. METHODS: Bone marrow aspirates were harvested from the distal femur during arthroscopic knee surgery in 26 patients. Twenty-five matched control subjects were selected to evaluate for increased incidence of complications. CTPs were isolated using a rapid method designed for use in the OR compared with 2 accepted methods. Cytochemical and molecular analysis was used to assess osteogenic potential. RESULTS: Osteogenic potential of the CTPs was confirmed by reverse transcription polymerase chain reaction analysis and cellular staining. Bone marrow was successfully aspirated in 25 cases, with 3 incidences of stiffness in the aspirate group compared with 2 in the control group, 1 incidence of a wound irregularity in the aspirate group compared with 1 in the control group, and 3 incidences of hemarthrosis/persistent effusion in the aspirate group compared with 1 in the control group. The rate of complications for the aspirate group was 36% compared with 25% in the control group. CONCLUSIONS: Our intention was to develop a technique for extracting and purifying bone marrow so that the orthopaedic surgeon would have a simple, safe, and efficient process by which to isolate CTPs during arthroscopic knee surgery. This method of aspiration did not lead to a significant increase in complications. Further bone marrow aspirate was successfully purified in the OR, with only a slight increase in surgery time, and resulted in a fractionated layer rich with CTPs. These cells showed osteogenic potential, as evidenced by their osteoblastic differentiation. These CTPs may have future use in enhancing the incorporation of the graft into the bone. LEVEL OF EVIDENCE: Level III, matched case-control study. PMID: 21996407 [PubMed - indexed for MEDLINE]
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Related Articles The effect of the addition of adipose-derived mesenchymal stem cells to a meniscal repair in the avascular zone: an experimental study in rabbits. Arthroscopy. 2011 Dec;27(12):1688-96 Authors: Ruiz-Ibán MÁ, Díaz-Heredia J, García-Gómez I, Gonzalez-Lizán F, Elías-Martín E, Abraira V Abstract PURPOSE: To determine whether adipose-derived mesenchymal stem cells (ASCs) affect the healing rate of meniscal lesions sutured in the avascular zone in rabbits. METHODS: Four groups were used. In group A (n = 12) a short, 5-mm-long longitudinal lesion in the avascular zone of the anterior horn of the medial meniscus was created and immediately sutured. In group B (n = 8) the same short lesion was created but suture was delayed 3 weeks. In group C (n = 12) a larger, 15-mm-long lesion that spanned the whole meniscus was created and sutured immediately. In group D (n = 8) the same large lesion was sutured 3 weeks later. Both knees in each rabbit were used: 1 served as the control, and in the other, 1 × 10(5) allogeneic ASCs marked with bromodeoxyuridine were placed in the lesion immediately before suturing. The animals were killed at 12 weeks. RESULTS: In group A (short lesion, acute repair) 6 of 12 ASC-treated menisci and 0 of 12 controls had some healing (P = .014). In group B (short lesion, delayed repair) 2 of 8 ASC-treated menisci and 1 of 8 controls had some healing (P = .5). In group C (long lesion, acute repair) 6 of 12 ASC-treated menisci and 0 of 12 controls had some healing (P = .014). In group D (long lesion, delayed repair) 4 of 8 ASC-treated menisci and 0 of 8 controls had some healing (P = .07). The addition of ASCs increased the healing rate (odds ratio, 32 [range, 3.69 to 277]; P = .002). The histologic analysis of the healed zones identified well-formed meniscal fibrocartilage with persistence of cells derived from the ASCs (immunolocated with anti-bromodeoxyuridine antibodies). CONCLUSIONS: Adding ASCs to a repair in the avascular zone of rabbit menisci increases the chances of healing. Healing is improved in small and larger lesions. When suture is delayed, the effect is not as evident. CLINICAL RELEVANCE: In the future, ASCs might help in meniscal repair in the avascular zone. PMID: 22001734 [PubMed - indexed for MEDLINE]
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Related Articles Tissue engineering and regenerative medicine strategies in meniscus lesions. Arthroscopy. 2011 Dec;27(12):1706-19 Authors: Pereira H, Frias AM, Oliveira JM, Espregueira-Mendes J, Reis RL Abstract PURPOSE: The aim of this systematic review was to address tissue engineering and regenerative medicine (TERM) strategies applied to the meniscus, specifically (1) clinical applications, indications, results, and pitfalls and (2) the main trends in research assessed by evaluation of preclinical (in vivo) studies. METHODS: Three independent reviewers performed a search on PubMed, from 2006 to March 31, 2011, using the term "meniscus" with all of the following terms: "scaffolds," "constructs," "cells," "growth factors," "implant," "tissue engineering," and "regenerative medicine." Inclusion criteria were English language-written, original clinical research (Level of Evidence I to IV) and preclinical studies of TERM application in knee meniscal lesions. Reference lists and related articles on journal Web sites of selected articles were checked until prepublication for potential studies that could not be identified eventually by our original search. The modified Coleman Methodology score was used for study quality analysis of clinical trials. RESULTS: The PubMed search identified 286 articles (a similar search from 2000 to 2005 identified 161 articles). Non-English-language articles (n = 9), Level V publications (n = 19), in vitro studies (n = 118), and 102 studies not related to the topic were excluded. One reference was identified outside of PubMed. Thirty-eight references that met the inclusion criteria were identified from the original search. On the basis of our prepublication search, 2 other references were included. A total of 9 clinical and 31 preclinical studies were selected for further analysis. Of the clinical trials, 1 was classified as Level I, 2 as Level II, and 6 as Level IV. Eight referred to acellular scaffold implantation for partial meniscal replacement, and one comprised fibrin clot application. The mean modified Coleman Methodology score was 48.0 (SD, 15.7). Of the preclinical studies, 11 original works reported on studies using large animal models whereas 20 research studies used small animals. In these studies the experimental design favored cell-seeded scaffolds or scaffolds enhanced with growth factors (GFs) in attempts to improve tissue healing, as opposed to the plain acellular scaffolds that were predominant in clinical trials. Injection of mesenchymal stem cells and gene therapy are also presented as alternative strategies. CONCLUSIONS: Partial meniscal substitution using acellular scaffolds in selected patients with irreparable loss of tissue may be a safe and promising procedure. However, there is only 1 randomized controlled study supporting its application, and globally, many methodologic issues of published trials limit further conclusions. We registered a different trend in preclinical trials, with most considering augmentation of scaffolds by cells and/or GFs, as opposed to the predominantly acellular approach in clinical trials. Different TERM approaches to enhance meniscal repair or regeneration are in preclinical analysis, such as the use of mesenchymal stem cells, gene therapy, and GFs alone or in combination, and thus could be considered in the design of subsequent trials. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies. PMID: 22019234 [PubMed - indexed for MEDLINE]
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Related Articles An overview of the different approaches used in the development of meniscal tissue engineering. Curr Stem Cell Res Ther. 2012 Mar;7(2):157-63 Authors: Malvankar SM, Khan WS Abstract The menisci are important fibrocartilaginous structures which give lubrication, shock absorption, nutrition and stabilisation to the knee joint, and also help transfer load. The meniscus' extracellular matrix possesses a complex architecture which is not uniform throughout the tissue. The inner third of the meniscus is composed of hyaline cartilage and the outer meniscus is composed of fibrocartilage. In a mature meniscus only the outer 10-25% is vascularised. There are various types of pathology associated with the meniscus. Previously, surgical techniques used to be considered as conventional treatment for meniscal lesions. However lesions in the avascular regions of the meniscus would rarely heal appropriately. It has been found that total menisectomies in patients may increase their chance of suffering from osteoarthritis in the future. Meniscal tissue engineering has been developed in an attempt to help improve the healing potential of avascular meniscal regions. Many different concepts and approaches have been tried and tested, such as the application of natural and synthetic scaffolds, mesenchymal stem cells, growth factors, fibrin glue and more. The objective of this review is to summarise the different approaches that have been used in the development of meniscal tissue engineering. The focus of this review is to evaluate the strengths and weaknesses of the studies that have been carried out, and from there determine what we have learnt from them in order to further the development in meniscal tissue engineering. PMID: 22023637 [PubMed - indexed for MEDLINE]
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Related Articles Current concepts of articular cartilage repair. Acta Orthop Belg. 2011 Dec;77(6):709-26 Authors: Schindler OS Abstract Articular cartilage provides a vital function in the homeostasis of the joint environment. It possesses unique mechanical properties, allowing for the maintenance of almost frictionless motion over a lifetime. However, cartilage is vulnerable to traumatic injury and due to its poor vascularity and inability to access mesenchymal stem cells, unable to facilitate a satisfactory healing response. Untreated chondral defects are thus likely to predispose patients to the development of osteoarthritis. Reconstitution and repair of articular cartilage is dependent on the neosynthesis or implantation of cartilage matrix elements, a goal which can be achieved through a variety of surgical means. Commonly used repair techniques include marrow stimulation, structural osteo-articular autografts or chondrocyte implantation. Despite substantial differences in the complexity and technical application of each method, all are united in the endeavour to restore joint function and prevent joint degeneration. Anyone attempting to treat cartilage defects must possess a basic understanding of the physiology of cartilage growth, and relevant factors affecting cartilage healing and repair. Furthermore, knowledge of the biomechanics and kinematics of the knee are essential in order to appreciate the forces acting on joint surfaces and repair tissues. Although clinical success is dependent on appropriate patient selection, accurate clinical assessment, definition of root causes and application of the right choice of treatment modality, the ultimate outcome of any intervention remains heavily reliant on the surgeon's proficiency in the technical aspects of the chosen surgical procedure. PMID: 22308614 [PubMed - indexed for MEDLINE]
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Related Articles Arthroscopic, histological and MRI analyses of cartilage repair after a minimally invasive method of transplantation of allogeneic synovial mesenchymal stromal cells into cartilage defects in pigs. Cytotherapy. 2012 Mar;14(3):327-38 Authors: Nakamura T, Sekiya I, Muneta T, Hatsushika D, Horie M, Tsuji K, Kawarasaki T, Watanabe A, Hishikawa S, Fujimoto Y, Tanaka H, Kobayashi E Abstract BACKGROUND AIMS: Transplantation of synovial mesenchymal stromal cells (MSCs) may induce repair of cartilage defects. We transplanted synovial MSCs into cartilage defects using a simple method and investigated its usefulness and repair process in a pig model. METHODS: The chondrogenic potential of the porcine MSCs was compared in vitro. Cartilage defects were created in both knees of seven pigs, and divided into MSCs treated and non-treated control knees. Synovial MSCs were injected into the defect, and the knee was kept immobilized for 10 min before wound closure. To visualize the actual delivery and adhesion of the cells, fluorescence-labeled synovial MSCs from transgenic green fluorescent protein (GFP) pig were injected into the defect in a subgroup of two pigs. In these two animals, the wounds were closed before MSCs were injected and observed for 10 min under arthroscopic control. The defects were analyzed sequentially arthroscopically, histologically and by magnetic resonance imaging (MRI) for 3 months. RESULTS: Synovial MSCs had a higher chondrogenic potential in vitro than the other MSCs examined. Arthroscopic observations showed adhesion of synovial MSCs and membrane formation on the cartilage defects before cartilage repair. Quantification analyses for arthroscopy, histology and MRI revealed a better outcome in the MSC-treated knees than in the non-treated control knees. CONCLUSIONS: Leaving a synovial MSC suspension in cartilage defects for 10 min made it possible for cells to adhere in the defect in a porcine cartilage defect model. The cartilage defect was first covered with membrane, then the cartilage matrix emerged after transplantation of synovial MSCs. PMID: 22309371 [PubMed - indexed for MEDLINE]
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Related Articles Interruption of glycosphingolipid synthesis enhances osteoarthritis development in mice. Arthritis Rheum. 2012 Aug;64(8):2579-88 Authors: Seito N, Yamashita T, Tsukuda Y, Matsui Y, Urita A, Onodera T, Mizutani T, Haga H, Fujitani N, Shinohara Y, Minami A, Iwasaki N Abstract OBJECTIVE: Glycosphingolipids (GSLs) are ubiquitous membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions. GSL expression is decreased in the articular cartilage of humans with osteoarthritis (OA). This study was undertaken to determine the functional role of GSLs in cartilage metabolism related to OA pathogenesis in mice. METHODS: We generated mice with knockout of the chondrocyte-specific Ugcg gene, which encodes an initial enzyme of major GSL synthesis, using the Cre/loxP system (Col2-Ugcg(-/-) mice). In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of GSLs on the cartilage degradation process. RESULTS: Although Col2-Ugcg(-/-) mice developed and grew normally, OA changes in these mice were dramatically enhanced with aging, through the overexpression of matrix metalloproteinase 13 and chondrocyte apoptosis, compared to their wild-type (WT) littermates. Col2-Ugcg(-/-) mice showed more severe instability-induced pathologic OA in vivo and interleukin-1α (IL-1α)-induced cartilage degradation in vitro. IL-1α stimulation of chondrocytes from WT mice significantly increased Ugcg messenger RNA expression and up-regulated GSL metabolism. CONCLUSION: Our results indicate that GSL deficiency in mouse chondrocytes enhances the development of OA. However, this deficiency does not affect the development and organization of cartilage tissue in mice at a young age. These findings indicate that GSLs maintain cartilage molecular metabolism and prevent disease progression, although GSLs are not essential for chondrogenesis of progenitor and stem cells and cartilage development in young mice. GSL metabolism in the cartilage is a potential target for developing a novel treatment for OA. PMID: 22391889 [PubMed - indexed for MEDLINE]
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Related Articles Effects of intra-articular administration of autologous bone marrow aspirate on healing of full-thickness meniscal tear: an experimental study on sheep. Acta Orthop Traumatol Turc. 2012;46(1):61-7 Authors: Duygulu F, Demirel M, Atalan G, Kaymaz FF, Kocabey Y, Dülgeroğlu TC, Candemir H Abstract OBJECTIVE: The aim of this study was to evaluate the effects of bone marrow-derived mesenchymal stem cell and bone marrow elements on the healing of meniscal tears. METHODS: This study was performed on twelve, 2-year-old male Tahirova sheep. In each subject, one knee was used for experiment purposes and the other knee was used as a control. After creating a longitudinal full-thickness tear in the red-white zone of the medial meniscus, aspirated autologous bone marrow material was injected into the tear site in the experiment group. The control group received no intervention for secondary healing. RESULTS: In the macroscopic evaluation of meniscus, a bridging reparation tissue and adhesion were observed between the rims of the tear in the experiment group. There was no statistical difference in collagen fibril formation between the groups (p=0.16). There was significantly more neovascularization in the experiment group than the control group (p=0.003). The cell count was also a significantly higher in the experiment group (p=0.004) and formation of cartilage plaques was more frequent in the experiment group (p=0.016). There was no evidence suggesting intrinsic repair in the meniscus of control group by light and electron microscopy. CONCLUSION: An injection of bone marrow into the meniscus tear site improves healing in a meniscal tear model as demonstrated by both light and electron microscopic findings. PMID: 22441454 [PubMed - indexed for MEDLINE]
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Related Articles Adult bone marrow stem cells in cartilage therapy. Acta Med Indones. 2012 Jan;44(1):62-8 Authors: Lubis AM, Lubis VK Abstract Cartilage defect rarely heals spontaneously since cartilage tissue is poorly vascularized and the lesion usually does not penetrate to subchondral bone, and hence it does not have access to progenitor cells of bone marrow. Severe cartilage damage may lead to osteoarthritis (OA). Current surgical and non-surgical therapeutic interventions in OA are limited to symptom relief and/or repair of focal lesion, and later a total knee replacement is still necessary. Cell therapy with chondrocyte implantation requires healthy cartilage for donor of the cells. Adult mesenchymal stem cells (MSCs) have the ability to differentiate into chondrogenic lineage. They can readily be isolated from bone marrow as well as many other adult tissues and have an extensive proliferation capacity. Therefore, MSCs may offer a great potential to be developed as an alternative for cell-based articular cartilage therapy. PMID: 22451188 [PubMed - indexed for MEDLINE]
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Related Articles Implantation of allogenic synovial stem cells promotes meniscal regeneration in a rabbit meniscal defect model. J Bone Joint Surg Am. 2012 Apr 18;94(8):701-12 Authors: Horie M, Driscoll MD, Sampson HW, Sekiya I, Caroom CT, Prockop DJ, Thomas DB Abstract BACKGROUND: Indications for surgical meniscal repair are limited, and failure rates remain high. Thus, new ways to augment repair and stimulate meniscal regeneration are needed. Mesenchymal stem cells are multipotent cells present in mature individuals and accessible from peripheral connective tissue sites, including synovium. The purpose of this study was to quantitatively evaluate the effect of implantation of synovial tissue-derived mesenchymal stem cells on meniscal regeneration in a rabbit model of partial meniscectomy. METHODS: Synovial mesenchymal stem cells were harvested from the knee of one New Zealand White rabbit, expanded in culture, and labeled with a fluorescent marker. A reproducible 1.5-mm cylindrical defect was created in the avascular portion of the anterior horn of the medial meniscus bilaterally in fifteen additional rabbits. Allogenic synovial mesenchymal stem cells suspended in phosphate-buffered saline solution were implanted into the right knees, and phosphate-buffered saline solution alone was placed in the left knees. Meniscal regeneration was evaluated histologically at four, twelve, and twenty-four weeks for (1) quantity and (2) quality (with use of an established three-component scoring system). A similar procedure was performed in four additional rabbits with use of green fluorescent protein-positive synovial mesenchymal stem cells for the purpose of tracking progeny following implantation. RESULTS: The quantity of regenerated tissue in the group that had implantation of synovial mesenchymal stem cells was greater at all end points, reaching significance at four and twelve weeks (p < 0.05). Tissue quality scores were also superior in knees treated with mesenchymal stem cells compared with controls at all end points, achieving significance at twelve and twenty-four weeks (3.8 versus 2.8 at four weeks [p = 0.29], 5.7 versus 1.7 at twelve weeks [p = 0.008], and 6.0 versus 3.9 at twenty-four weeks [p = 0.021]). Implanted cells adhered to meniscal defects and were observed in the regenerated tissue, where they differentiated into type-I and II collagen-expressing cells, at up to twenty-four weeks. CONCLUSIONS: Synovial mesenchymal stem cells adhere to sites of meniscal injury, differentiate into cells resembling meniscal fibrochondrocytes, and enhance both quality and quantity of meniscal regeneration. PMID: 22517386 [PubMed - indexed for MEDLINE]
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Related Articles Surgical options for meniscal replacement. J Am Acad Orthop Surg. 2012 May;20(5):265-72 Authors: Brophy RH, Matava MJ Abstract As a result of biologic issues and technical limitations, repair of the meniscus is indicated for unstable, peripheral vertical tears; most other types of meniscal tears that are degenerative, significantly traumatized, and/or located in an avascular area of the meniscus are managed with partial meniscectomy. Options to restore the meniscus range from allograft transplantation to the use of synthetic technologies. Recent studies demonstrate good long-term outcomes from meniscal allograft transplantation, although the indications and techniques continue to evolve and the long-term chondroprotective potential has yet to be determined. Several synthetic implants, none of which has US Food and Drug Administration approval, have shown some promise for replacing part or all of the meniscus, including the collagen meniscal implant, hydrogels, and polymer scaffolds. PMID: 22553098 [PubMed - indexed for MEDLINE]
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Related Articles Management of focal chondral lesion in the knee joint. Knee Surg Relat Res. 2011 Dec;23(4):185-96 Authors: Seo SS, Kim CW, Jung DW Abstract Articular cartilage does not contain vascular, nervous and lymphatic tissue and chondrocytes hardly participate in the healing or repair process of chondral tissue because of being surrounded by plenty of extracellular matrix. Therefore, the injury to articular cartilage frequently requires an operative treatment. The goal of surgical repair of articular cartilage is to regenerate nearly normal chondral tissue and prevent degenerative arthritis caused by the articular cartilage defect. Microfracture is a kind of cartilage repair procedure that makes a fibrin clot containing mesenchymal stem cells in the chondral lesion. Microfracture is a simple procedure but it has a disadvantage that the repaired tissue is fibrocartilage. Autologous chondrocyte implantation has an advantage that it implants fully differentiated chondrocytes to the lesion, which theoretically produces hyaline cartilage. Its disadvantages are that it is a two stage and a costly procedure. Osteochondral autograft transplantation is a one stage procedure and repairs the lesion with hyaline cartilage. But its limitation is the lack of donor site availability. Surgeons who understand the theoretical background, indications, surgical methods, rehabilitation, complications, and clinical course of cartilage repair procedures can achieve the goal of preventing degenerative arthritis. PMID: 22570833 [PubMed]
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Related Articles Nontraditional modification to articular cartilage. J Knee Surg. 2012 Mar;25(1):31-6 Authors: Karas V, Ghodadra N, Kroin E, Cole BJ Abstract Biomechanical imbalance, trauma, and age-related degeneration often result in chondral lesions, which may lead to overt osteoarthritis over time. Such cartilage pathology is frequently accompanied by persistent pain and loss of normal joint function. As a result, patients who suffer from biologically active articular cartilage lesions are often unable to function in both high level activities and exhibit compromised activities of daily living. The limited potential for self-regeneration of hyaline cartilage has led to the emergence of new technologies to solve this difficult clinical problem. Treatment of arthritis and chondral lesions includes alleviation of pain and return of function through pharmacologic intervention and/or attempts at cartilage reparative, restorative and reconstructive options. PMID: 22624245 [PubMed - indexed for MEDLINE]
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Related Articles Hyaluronic acid-binding scaffold for articular cartilage repair. Tissue Eng Part A. 2012 Dec;18(23-24):2497-506 Authors: Unterman SA, Gibson M, Lee JH, Crist J, Chansakul T, Yang EC, Elisseeff JH Abstract Hyaluronic acid (HA) is an extracellular matrix molecule with multiple physical and biological functions found in many tissues, including cartilage. HA has been incorporated in a number of biomaterial and scaffold systems. However, HA in the material may be difficult to control if it is not chemically modified and chemical modification of HA may negatively impact biological function. In this study, we developed a poly(ethylene glycol) hydrogel with noncovalent HA-binding capabilities and evaluated its ability to support cartilage formation in vitro and in an articular defect model. Chondrogenic differentiation of mesenchymal stem cells encapsulated in the HA-interactive scaffolds containing various amounts of exogenous HA was evaluated. The HA-binding hydrogel without exogenous HA produced the best cartilage as determined by biochemical content (glysocaminoglycan and collagen), histology (Safranin O and type II collagen staining), and gene expression analysis for aggrecan, type I collagen, type II collagen, and sox-9. This HA-binding formulation was then translated to an osteochondral defect model in the rat knee. After 6 weeks, histological analysis demonstrated improved cartilage tissue production in defects treated with the HA-interactive hydrogel compared to noninteractive control scaffolds and untreated defects. In addition to the tissue repair in the defect space, the Safranin O staining in cartilage tissue surrounding the defect was greater in treatment groups where the HA-binding scaffold was applied. In sum, incorporation of a noncovalent HA-binding functionality into biomaterials provides an ability to interact with local or exogenous HA, which can then impact tissue remodeling and ultimately new tissue production. PMID: 22724901 [PubMed - indexed for MEDLINE]
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Related Articles The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol. 2012 Jun;47(6):458-64 Authors: Al Faqeh H, Nor Hamdan BM, Chen HC, Aminuddin BS, Ruszymah BH Abstract In recent years, the use of bone marrow mesenchymal stem cell (BMSC) implantation has provided an alternative treatment for osteoarthritis. The objective of this study is to determine whether or not an intra-articular injection of a single dose of autologous chondrogenic induced BMSC could retard the progressive destruction of cartilage in a surgically induced osteoarthritis in sheep. Sheep BMSCs were isolated and divided into two groups. One group was cultured in chondrogenic media containing (Ham's F12:DMEM, 1:1) FD+1% FBS+5 ng/ml TGFβ3+50 ng/ml IGF-1 (CM), and the other group was cultured in the basal media, FD+10% FBS (BM). The procedure for surgically induced osteoarthritis was performed on the donor sheep 6 weeks prior to intra-articular injection into the knee joint of a single dose of BMSC from either group, suspended in 5 ml FD at density of 2 million cells/ml. The control groups were injected with basal media, without cells. Six weeks after injection, gross evidence of retardation of cartilage destruction was seen in the osteoarthritic knee joints treated with CM as well as BM. No significant ICRS (International Cartilage Repair Society) scoring was detected between the two groups with cells. However macroscopically, meniscus repair was observed in the knee joint treated with CM. Severe osteoarthritis and meniscal injury was observed in the control group. Interestingly, histologically the CM group demonstrated good cartilage histoarchitecture, thickness and quality, comparable to normal knee joint cartilage. As a conclusion, intra-articular injection of a single dose of BMSC either chondrogenically induced or not, could retard the progression of osteoarthritis (OA) in a sheep model, but the induced cells indicated better results especially in meniscus regeneration. PMID: 22759409 [PubMed - indexed for MEDLINE]
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Related Articles Human placenta-derived mesenchymal stem cells with silk fibroin biomaterial in the repair of articular cartilage defects. Cell Reprogram. 2012 Aug;14(4):334-41 Authors: Li F, Chen YZ, Miao ZN, Zheng SY, Jin J Abstract Cartilage tissue engineering requires a porous biodegradable scaffold and nonimmunogenic cells with chondrogenic potential. In this study, the ability of the placenta-derived mesenchymal stem cells (PMSCs) to grow on silk fibroin (SF) biomaterial was determined, and the potential of a SF biomaterial serving as a delivery vehicle for human PMSCs in a rabbit articular cartilage defects model was evaluated. Human PMSCs were maintained in vitro in an allogeneic mixed lymphocyte reactions (MLR) system to investigate the suppressive effects on T cell proliferation. A total of 12 healthy adult New Zealand rabbits were implanted with a PMSC/SF biomaterial complex after articular cartilage defects of the femoral condyle in the knee were established. The repair of the articular cartilage defects was observed after 4 weeks, 8 weeks, and 12 weeks. Results from the MLR indicated that human PMSCs inhibited rabbit T cell responses. Knee damage was repaired by the newly formed hyaline cartilage, and within 12 weeks there was neither degeneration nor infiltration with lymphocytes or leukocytes, and no silk fibroin biomaterial residue was detected. In conclusion, the silk fibroin biomaterial can be applied as a new scaffold for cartilage tissue engineering, and implantation of human PMSCs on the cartilage can enhance repair of articular cartilage defects in a rabbit model. PMID: 22816556 [PubMed - indexed for MEDLINE]
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Related Articles Intra-articular delivery of purified mesenchymal stem cells from C57BL/6 or MRL/MpJ superhealer mice prevents posttraumatic arthritis. Cell Transplant. 2013;22(8):1395-408 Authors: Diekman BO, Wu CL, Louer CR, Furman BD, Huebner JL, Kraus VB, Olson SA, Guilak F Abstract Joint injury dramatically enhances the onset of osteoarthritis (OA) and is responsible for an estimated 12% of OA. Posttraumatic arthritis (PTA) is especially common after intra-articular fracture, and no disease-modifying therapies are currently available. We hypothesized that the delivery of mesenchymal stem cells (MSCs) would prevent PTA by altering the balance of inflammation and regeneration after fracture of the mouse knee. Additionally, we examined the hypothesis that MSCs from the MRL/MpJ (MRL) "superhealer" mouse strain would show increased multilineage and therapeutic potentials as compared to those from C57BL/6 (B6) mice, as MRL mice have shown exceptional in vivo regenerative abilities. A highly purified population of MSCs was prospectively isolated from bone marrow using cell surface markers (CD45-/TER119-/PDGFRα+/Sca-1+). B6 MSCs expanded greater than 100,000-fold in 3 weeks when cultured at 2% oxygen and displayed greater adipogenic, osteogenic, and chondrogenic differentiation as compared to MRL MSCs. Mice receiving only a control saline injection after fracture demonstrated PTA after 8 weeks, but the delivery of 10,000 B6 or MRL MSCs to the joint prevented the development of PTA. Cytokine levels in serum and synovial fluid were affected by treatment with stem cells, including elevated systemic interleukin-10 at several time points. The delivery of MSCs did not reduce the degree of synovial inflammation but did show increased bone volume during repair. This study provides evidence that intra-articular stem cell therapy can prevent the development of PTA after fracture and has implications for possible clinical interventions after joint injury before evidence of significant OA. PMID: 22889498 [PubMed - indexed for MEDLINE]
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Related Articles Science to practice: can macrophage infiltration serve as a surrogate marker for stem cell viability? Radiology. 2012 Sep;264(3):619-20 Authors: Bulte JW Abstract Following in vivo prelabeling of host macrophages with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, it was shown that their magnetic resonance (MR) imaging–visible migration into knee implants of scaffolded adipose-derived stem cells (ADSCs) undergoing apoptosis can serve as a surrogate marker of stem cell death. PMID: 22919033 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell therapy in the sports knee: where are we in 2011? Sports Health. 2012 May;4(3):252-7 Authors: Dave LY, Nyland J, McKee PB, Caborn DN Abstract BACKGROUND: The relationship between biological tissue healing following knee injury or surgery and long-term clinical outcome has come to the forefront of sports medicine practice. This has led many knee surgeons to incorporate biologically mediated healing factors into the management of knee injuries. In particular, the clinical use of mesenchymal stem cells has opened new horizons. EVIDENCE ACQUISITION: Relevant studies were identified through a search of PubMed from January 2000 to April 2011, combining the term mesenchymal stem cells with articular cartilage, anterior cruciate ligament, and meniscus. Relevant citations from the reference lists of selected studies were also reviewed. RESULTS: Knee injury treatment with mesenchymal stem cells shows potential. Most reports represent animal model studies; few advances have been translated to human clinical applications. CONCLUSION: Mesenchymal stem cell use to promote healing following knee injury is likely to increase. There are scientific methodological concerns and ethical and legal issues regarding mesenchymal stem cell use for treating knee injuries. PMID: 23016095 [PubMed]
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Related Articles A novel, minimally-invasive technique of cartilage repair in the human knee using arthroscopic microfracture and injections of mesenchymal stem cells and hyaluronic acid--a prospective comparative study on safety and short-term efficacy. Ann Acad Med Singapore. 2012 Nov;41(11):511-7 Authors: Lee KB, Wang VT, Chan YH, Hui JH Abstract INTRODUCTION: Most current cell-based cartilage repair techniques require some form of scaffolds and 2 separate surgical procedures. We propose a novel, scaffold-less technique of cartilage repair in the human knee that combines arthroscopic microfracture and outpatient intra-articular injections of autologous bone marrow-derived mesenchymal stem cells (MSCs) and hyaluronic acid (HA). MATERIALS AND METHODS: Seventy matched (age, sex, lesion size) knees with symptomatic cartilage defects underwent cartilage repair with the proposed technique (n = 35) or an open technique (n = 35) in which the MSCs were implanted beneath a sutured periosteal patch over the defect. Prospective evaluation of both groups were performed using the International Cartilage Repair Society (ICRS) Cartilage Injury Evaluation Package, which included questions from the Short-Form (SF-36) Health Survey, International Knee Documentation Committee (IKDC) subjective knee evaluation form, Lysholm knee scale, and Tegner activity level scale. Postoperative magnetic resonance imaging (MRI) evaluation was also performed at 1 year for most patients. RESULTS: There were no clinically significant adverse events reported through the course of our study. At the fi nal follow-up (mean = 24.5 months), there was significant improvement in mean IKDC, Lysholm, SF-36 physical component score and visual analogue pain scores in both treatment groups. CONCLUSION: In the short term, the results of this novel technique are comparable to the open procedure with the added advantages of being minimally invasive and requiring only a single operation under general anaesthesia. Its safety has been validated and its efficacy is currently being evaluated in an ongoing randomised controlled trial. PMID: 23235728 [PubMed - indexed for MEDLINE]
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Related Articles Growth factors and stem cells for the management of anterior cruciate ligament tears. Open Orthop J. 2012;6:525-30 Authors: Rizzello G, Longo UG, Petrillo S, Lamberti A, Khan WS, Maffulli N, Denaro V Abstract The anterior cruciate ligament (ACL) is fundamental for the knee joint stability. ACL tears are frequent, especially during sport activities, occurring mainly in young and active patients. Nowadays, the gold standard for the management of ACL tears remains the surgical reconstruction with autografts or allografts. New strategies are being developed to resolve the problems of ligament grafting and promote a physiological healing process of ligamentous tissue without requiring surgical reconstruction. Moreover, these strategies can be applicable in association surgical reconstruction and may be useful to promote and accelerate the healing process. The use of growth factors and stem cells seems to offer a new and fascinating solution for the management of ACL tears. The injection of stem cell and/or growth factors in the site of ligamentous injury can potentially enhance the repair process of the physiological tissue. These procedures are still at their infancy, and more in vivo and in vitro studies are required to clarify the molecular pathways and effectiveness of growth factors and stem cells therapy for the management of ACL tears. This review aims to summarize the current knowledge in the field of growth factors and stem cells for the management of ACL tears. PMID: 23248722 [PubMed]
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Related Articles Therapeutic advantage in selective ligament augmentation for partial tears of the anterior cruciate ligament: results in an animal model. Am J Sports Med. 2013 Feb;41(2):365-73 Authors: Mifune Y, Ota S, Takayama K, Hoshino Y, Matsumoto T, Kuroda R, Kurosaka M, Fu FH, Huard J Abstract BACKGROUND: As a result of recent studies describing the double-bundle anterior cruciate ligament (ACL), selected ACL augmentation procedures, either anteromedial (AM) or posterolateral (PL), have been introduced as the treatment of choice for partial ACL ruptures. The preserved mechanoreceptor and vascularity of the remnant ACL are considered to provide additional biological benefits. Although enhanced knee joint proprioception in ACL augmented patients has been previously reported, there is no study assessing biological healing advantages of the graft after the ACL augmentation procedure. HYPOTHESIS: Selected ACL augmentation for partial tears can accelerate the healing process of the grafted tendon, which promotes better biomechanical recovery of the tendon, compared with conventional ACL reconstruction of complete tears. STUDY DESIGN: Controlled laboratory study. METHODS: Two rat models were established in this study: an ACL augmentation partial tear model and conventional ACL reconstruction for a complete tear. Biological assessments of cellularity and angiogenesis were measured by hematoxylin and eosin staining and immunostaining, respectively. Additionally, rat-specific type III collagen and α-smooth muscle actin were evaluated by immunohistochemical staining to analyze the healing process, whereas anti-rat neurofilament antigen was assessed to examine proprioceptive recovery. Biological assessments of the augmented and reconstructed grafts were conducted postoperatively at week 2, whereas biomechanical testing was performed postoperatively at week 8. RESULTS: An increase in cellularity and angiogenesis was observed in the augmented grafts compared with the conventionally reconstructed grafts. Also, increased amounts of rat-specific type III collagen, α-smooth muscle actin, and anti-rat neurofilament antigen were expressed in the augmented grafts. Biomechanical testing showed that failure to load was significantly higher in the augmentation group compared with the conventional reconstruction group (augmentation, 15.9 ± 1.0; reconstruction, 7.0 ± 1.3; P < .01). CLINICAL RELEVANCE: Selected ACL augmentation could be a good choice for the repair of partial ACL injury by preserving the uninjured portion of the ACL, which in turn could maintain the anatomic position of the ligament and its biomechanical function. PMID: 23299851 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013 Aug;21(8):1717-29 Authors: Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E Abstract PURPOSE: The 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: Despite 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 EVIDENCE: IV. PMID: 23306713 [PubMed - indexed for MEDLINE]
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Related Articles A systematic review of tissue engineered meniscus: cell-based preclinical models. Curr Stem Cell Res Ther. 2013 May;8(3):222-31 Authors: Haddad B, Pakravan AH, Konan S, Adesida A, Khan W Abstract Meniscal injuries are one of the common sports injuries and their natural healing is limited. Removal of injured meniscus alters knee biomechanics and predisposes patients to osteoarthritis. Tissue engineered meniscus provides a novel approach for the treatment of severe meniscus injury. The aim of this review is to review preclinical studies that used cell based approaches for tissue engineered meniscus. Studies were assessed for inclusion following a search in PubMed, UK PubMed central and Embase. All preclinical studies that used cell based approaches for meniscus regeneration were included in the study. Nineteen articles that used cellular approaches were reviewed. The cell types used were mesenchymal stem cells (derived from bone marrow or synovium), meniscal fibrochondrocytes, chondrocytes and bone marrow stromal cells. One study used xenogeneic bone marrow derived mesenchymal stem cells. Sixteen out of nineteen studies showed better tissue regeneration with cell based approaches when compared to acellular controls. The review included preclinical studies. The diversity of the studies made it impossible to adhere to full guidelines or perform a meta-analysis. Overall,experiments have demonstrated superior tissue integration and favourable biochemical properties of the regenerated tissues compared to acellular techniques. Few approaches however, have measured the chondroprotective ability at preclinical testing. PMID: 23317471 [PubMed - indexed for MEDLINE]
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Related Articles A systematic review of tissue engineered meniscus and replacement strategies: preclinical models. Curr Stem Cell Res Ther. 2013 May;8(3):232-42 Authors: Haddad B, Haddad B, Konan S, Adesida A, Khan WS Abstract Meniscal injuries are among the common sports injuries and their natural healing is limited. Removal of injured meniscus impairs normal knee function and predisposes patients to osteoarthritis. Tissue engineering and replacement strategies provide a novel approach for the treatment of severe meniscus injury. The aim of this article is to review preclinical studies that used approaches for meniscal replacement including growth factors, synthetic and tissue engineered scaffolds and non-meniscal autografts. Medline, EMBASE and UK PubMed search was performed and articles were assessed for inclusion. Included articles were summarised and categorised. Forty seven articles matched the inclusion criteria.The studies were classified according to the approaches used for meniscus replacement. Overall most experiments have shown good tissue integration and biochemical properties of the regenerated tissues. However, only few approaches have demonstrated satisfactory chondroprotective function. PMID: 23317472 [PubMed - indexed for MEDLINE]
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Related Articles Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial. Arthroscopy. 2013 Apr;29(4):684-94 Authors: Saw KY, Anz A, Siew-Yoke Jee C, Merican S, Ching-Soong Ng R, Roohi SA, Ragavanaidu K Abstract PURPOSE: The purpose of this study was to compare histologic and magnetic resonance imaging (MRI) evaluation of articular cartilage regeneration in patients with chondral lesions treated by arthroscopic subchondral drilling followed by postoperative intra-articular injections of hyaluronic acid (HA) with and without peripheral blood stem cells (PBSC). METHODS: Fifty patients aged 18 to 50 years with International Cartilage Repair Society (ICRS) grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling; 25 patients each were randomized to the control (HA) and the intervention (PBSC + HA) groups. Both groups received 5 weekly injections commencing 1 week after surgery. Three additional injections of either HA or PBSC + HA were given at weekly intervals 6 months after surgery. Subjective IKDC scores and MRI scans were obtained preoperatively and postoperatively at serial visits. We performed second-look arthroscopy and biopsy at 18 months on 16 patients in each group. We graded biopsy specimens using 14 components of the International Cartilage Repair Society Visual Assessment Scale II (ICRS II) and a total score was obtained. MRI scans at 18 months were assessed with a morphologic scoring system. RESULTS: The total ICRS II histologic scores for the control group averaged 957 and they averaged 1,066 for the intervention group (P = .022). On evaluation of the MRI morphologic scores, the control group averaged 8.5 and the intervention group averaged 9.9 (P = .013). The mean 24-month IKDC scores for the control and intervention groups were 71.1 and 74.8, respectively (P = .844). One patient was lost to follow-up. There were no notable adverse events. CONCLUSIONS: After arthroscopic subchondral drilling into grade 3 and 4 chondral lesions, postoperative intra-articular injections of autologous PBSC in combination with HA resulted in an improvement of the quality of articular cartilage repair over the same treatment without PBSC, as shown by histologic and MRI evaluation. LEVEL OF EVIDENCE: Level II, randomized controlled trial (RCT). PMID: 23380230 [PubMed - indexed for MEDLINE]
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Related Articles Subtrochanteric fracture non-unions with implant failure managed with the "Diamond" concept. Injury. 2013 Jan;44 Suppl 1:S76-81 Authors: Giannoudis PV, Ahmad MA, Mineo GV, Tosounidis TI, Calori GM, Kanakaris NK Abstract BACKGROUND: Subtrochanteric femoral non-unions in the setting of failed metalwork pose a challenging clinical problem. This study assessed the clinical outcome of patients treated according to the principles of the "Diamond" concept. METHODS: Between 2007 and 2011 all patients presented with a subtrochanteric atrophic aseptic non-union in the setting of metalwork failure (broken cephalomedullary reconstruction nail), and treated in a single tertiary referral unit were included to this study. The hypertrophic and the non-unions of pathologic fractures were excluded. The revision strategy was based on the "Diamond concept"; optimisation of the mechanical and the biological environment (implantation of growth factor (rhBMP-7), scaffold (RIA bone graft from contralateral femur) and concentrated mesenchymal stem cells (MSCs) harvested from the iliac crest). The minimum follow up was 26 months (16-48). RESULTS: Fourteen patients met the inclusion criteria. A specific sequence of metalwork failure was noted with initial breakage of the distal locking screws followed by nail breakage at the lag screw level. The intraoperative examination of the removed nails revealed no gross structural damage indicative of inappropriate drilling at the time of the initial intramedullary nailing. Varus mal-alignment was present in the majority of the cases, with an average of 5.2 degrees (0-11). The average time to distal locking screw failure was 4.4 months (2-8.5) and nail failure was 6.5 months (4-10). The time to union after the revision surgery was 6.8 months (5-12). Complications included two deaths in elderly patients (due to unrelated causes), one pulmonary embolism, one myocardial infarction, one below the knee deep vein thrombosis and one blade plate failure that required further revision with double plating and grafting. CONCLUSION: Varus mal-alignment must be avoided in the initial stabilisation of subtrochanteric fractures. Distal locking screw failure is predictive of future fracture non-union and nail breakage. In the absence of sepsis, a single stage procedure based on the "Diamond concept" that simultaneously optimizes the mechanical and biological environment is a successful method for managing complex subtrochanteric atrophic non-unions with failed metalwork. PMID: 23351877 [PubMed - indexed for MEDLINE]
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Related Articles One-step arthroscopic technique for the treatment of osteochondral lesions of the knee with bone-marrow-derived cells: three years results. Musculoskelet Surg. 2013 Aug;97(2):145-51 Authors: Buda R, Vannini F, Cavallo M, Baldassarri M, Luciani D, Mazzotti A, Pungetti C, Olivieri A, Giannini S Abstract Osteochondral lesions of the knee (OLK) are a common cause of knee pain and associated diseases. A new bone-marrow-derived mesenchymal stem cells technique has been developed for the treatment of OLK. 30 patients with OLK underwent arthroscopic one-step procedure. The bone marrow was harvested from the patients' posterior iliac crest and arthroscopically implanted with a scaffold into the lesion site. Clinical inspection and MRI were performed. Mean International Knee Documentation Committee (IKDC) score before surgery was 29.9 ± 13.2 and 85.4 ± 4.2 at 29 ± 4.1 months (p < 0.0005), while Knee injury and Osteoarthritis Outcome Score (KOOS) before surgery was 35.1 ± 11.9 and 87.3 ± 7.3 at 29 ± 4.1 months (p < 0.0005). Control MRI and bioptic samples showed an osteochondral regeneration of the lesion site. The one-step technique appears to be a good and reliable option for treatment of OLK at three years of follow-up. Level of evidence Case series, Level IV. PMID: 23420394 [PubMed - in process]
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Related Articles Anterior cruciate ligament regeneration using mesenchymal stem cells and collagen type I scaffold in a rabbit model. Knee Surg Sports Traumatol Arthrosc. 2013 Mar 9; Authors: Figueroa D, Espinosa M, Calvo R, Scheu M, Vaisman A, Gallegos M, Conget P Abstract PURPOSE: The objective of this study was to determine whether using mesenchymal stem cells (MSC) seeded in a collagen type I scaffold would be sufficient to regenerate the torn anterior cruciate ligament (ACL). METHODS: Anterior cruciate ligament transection was performed on both knees in 10 New Zealand rabbits and then repaired with as follows: suture alone (suture-treated group, n = 6), suture associated with collagen type I scaffold (collagen type I scaffold-treated group, n = 8) or suture associated with autologous MSC seeded on collagen type I scaffold (MSC/collagen type I scaffold-treated group, n = 6). At 12-week post-intervention, the animals were killed and the ACLs were characterised macroscopically and histologically. Data of the 3 groups were against normal ACL (normal group, n = 10). RESULTS: Macroscopic observation found that in MSC/collagen type I scaffold group, 33 % of specimens showed a complete ACL regeneration, with a tissue similar to the normal ACL. Regeneration was not observed in the group treated with suture alone or associated with collagen type I scaffold without cells. In the latter, only a reparative attempt at the ends was observed. Histological analysis of the regenerated ACL showed a tissue with organised collagen and peripheric vessels. CONCLUSIONS: These results provide evidence that the use of MSC seeded in a collagen type I scaffold in the treatment of ACL injuries is associated with an enhancement of ligament regeneration. This MSC-based technique is a potentially attractive tool for improving the treatment of ACL ruptures. PMID: 23474696 [PubMed - as supplied by publisher]
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Related Articles Chitosan/poly(vinyl alcohol) hydrogel combined with Ad-hTGF-β1 transfected mesenchymal stem cells to repair rabbit articular cartilage defects. Exp Biol Med (Maywood). 2013 Jan;238(1):23-30 Authors: Qi BW, Yu AX, Zhu SB, Zhou M, Wu G Abstract The aim of this work is to explore the feasibility and therapeutic effect of repairing rabbit articular cartilage defects using thermo-sensitive chitosan/poly (vinyl alcohol) composite hydrogel engineered Ad-hTGF-β1-transfected bone marrow mesenchymal stem cells. Rabbit's bone marrow stromal cells (BMSCs) were obtained and cultured in vitro and transfected with a well-constructed Ad-hTGF-β1 vector, the cartilage phenotype of the transfected cells was tested by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Twenty-four New Zealand white rabbits with articular cartilage defects were randomly divided into four groups: group A was treated with CS/PVA gel and transfected BMSCs; group B received CS/PVA gel and un-transfected BMSCs; group C was treated with CS/PVA gel alone and group D was the untreated control group. Experimental animals of each group were killed at 16 weeks after operation. General observation, Masson's trichrome staining and collagen II immunohistological staining of the specimens were performed to evaluate the repair effect. The Wakitani scoring method was used to evaluate the repair effect. RT-PCR and Western blot confirmed that the hTGF-β1 gene was expressed in BMSCs and triggered the expression of specific markers of cartilage differentiation such as aggrecan mRNA and Collagen II in BMSCs after transfection with Ad-hTGF-β1. Sixteen weeks after operation, the defects in group A had smooth and flat surfaces, and the defects appeared to have completely healed, exhibiting almost the same color and texture as the surrounding cartilage. Masson's trichrome staining showed that the cell arrangement and density of regenerated cartilage tissue in group A was not significantly different from that of normal cartilage tissue. The immunohistochemical staining of Col II showed a strong expression in group A and weak expression in group B, but no expression in groups C and D. According to the Wakitani score, the difference between experimental group A and all of the other groups was statistically significant (P < 0.01). To conclude, as a thermosensitive and injectable scaffold material, CS/PVA gel engineered with BMSCs transfected with hTGF-β1 can effectively repair rabbit articular cartilage defects. PMID: 23479760 [PubMed - indexed for MEDLINE]
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Related Articles Reconstruction of cartilage with clonal mesenchymal stem cell-acellular dermal matrix in cartilage defect model in nonhuman primates. Int Immunopharmacol. 2013 Jul;16(3):399-408 Authors: Ma A, Jiang L, Song L, Hu Y, Dun H, Daloze P, Yu Y, Jiang J, Zafarullah M, Chen H Abstract OBJECTIVE: Articular cartilage defects are commonly associated with trauma, inflammation and osteoarthritis. Mesenchymal stem cell (MSC)-based therapy is a promising novel approach for repairing articular cartilage. Direct intra-articular injection of uncommitted MSCs does not regenerate high-quality cartilage. This study explored utilization of a new three-dimensional, selected chondrogenic clonal MSC-loaded monkey acellular dermal matrix (MSC-ADM) scaffold to repair damaged cartilage in an experimental model of knee joint cartilage defect in Cynomolgus monkeys. METHODS: MSCs were characterized for cell size, cell yield, phenotypes, proliferation and chondrogenic differentiation capacity. Chondrogenic differentiation assays were performed at different MSC passages by sulfated glycosaminoglycans (sGAG), collagen, and fluorescence activated cell sorter (FACS) analysis. Selected chondrogenic clonal MSCs were seeded onto ADM scaffold with the sandwich model and MSC-loaded ADM grafts were analyzed by confocal microscopy and scanning electron microscopy. Cartilage defects were treated with normal saline, clonal MSCs and clonal MSC-ADM grafts, respectively. The clinical parameters, and histological and immunohistochemical examinations were evaluated at weeks 8, 16, 24 post-treatment, respectively. RESULTS: Polyclonal and clonal MSCs could differentiate into the chondrogenic lineage after stimulation with suitable chondrogenic factors. They expressed mesenchymal markers and were negative for hematopoietic markers. Articular cartilage defects were considerably improved and repaired by selected chondrogenic clonal MSC-based treatment, particularly, in MSC-ADM-treated group. The histological scores in MSC-ADM-treated group were consistently higher than those of other groups. CONCLUSION: Our results suggest that selected chondrogenic clonal MSC-loaded ADM grafts could improve the cartilage lesions in Cynomolgus monkey model, which may be applicable for repairing similar human cartilage defects. PMID: 23499511 [PubMed - indexed for MEDLINE]
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Related Articles Stem cells in the knee. Arthroscopy. 2013 Apr;29(4):609-10 Authors: Lubowitz JH, Provencher MT, Poehling GG PMID: 23527590 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell-based tissue-engineering for treatment of meniscal tears in the avascular zone. J Biomed Mater Res B Appl Biomater. 2013 Oct;101(7):1133-42 Authors: Zellner J, Hierl K, Mueller M, Pfeifer C, Berner A, Dienstknecht T, Krutsch W, Geis S, Gehmert S, Kujat R, Dendorfer S, Prantl L, Nerlich M, Angele P Abstract Meniscal tears in the avascular zone have a poor self-healing potential, however partial meniscectomy predisposes the knee for early osteoarthritis. Tissue engineering with mesenchymal stem cells and a hyaluronan collagen based scaffold is a promising approach to repair meniscal tears in the avascular zone. 4 mm longitudinal meniscal tears in the avascular zone of lateral menisci of New Zealand White Rabbits were performed. The defect was left empty, sutured with a 5-0 suture or filled with a hyaluronan/collagen composite matrix without cells, with platelet rich plasma or with autologous mesenchymal stem cells. Matrices with stem cells were in part precultured in chondrogenic medium for 14 days prior to the implantation. Menisci were harvested at 6 and 12 weeks. The developed repair tissue was analyzed macroscopically, histologically and biomechanically. Untreated defects, defects treated with suture alone, with cell-free or with platelet rich plasma seeded implants showed a muted fibrous healing response. The implantation of stem cell-matrix constructs initiated fibrocartilage-like repair tissue, with better integration and biomechanical properties in the precultured stem cell-matrix group. A hyaluronan-collagen based composite scaffold seeded with mesenchymal stem cells is more effective in the repair avascular meniscal tear with stable meniscus-like tissue and to restore the native meniscus. PMID: 23564690 [PubMed - indexed for MEDLINE]
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Related Articles Intraarticular injection of synovial stem cells promotes meniscal regeneration in a rabbit massive meniscal defect model. J Orthop Res. 2013 Sep;31(9):1354-9 Authors: Hatsushika D, Muneta T, Horie M, Koga H, Tsuji K, Sekiya I Abstract We investigated whether single intraarticular injection of synovial MSCs enhanced meniscal regeneration in a rabbit massive meniscal defect model. Synovium were harvested from the knee joint of rabbits, and the colony-forming cells were collected. Two weeks after the anterior half of the medial menisci were excised in both knees, 1 × 10(7) MSCs in 100 μl PBS were injected into the right knee. The MSC and control groups were compared macroscopically and histologically at 1, 3, 4, and 6 months (n = 4). Articular cartilage of the medial femoral condyle was also evaluated histologically at 6 months. Multipotentiality of the colony-forming cells was confirmed. Injected MSCs labeled with DiI were detected and remained in the meniscal defect at 14 days. The size of meniscus in the MSC group was larger than that in the control group at 1 and 3 months. The difference of the size between the two groups was indistinct at 4 and 6 months. However, histological score was better in the MSC group than in the control group at 1, 3, 4, and 6 months. Macroscopically, the surface of the medial femoral condyle in the control group was fibrillated at 6 months, while looked close to intact in the MSC group. Histologically, defect or thinning of the articular cartilage with sclerosis of the subchondral bone was observed in the control group, contrarily articular cartilage and subchondral bone were better preserved in the MSC group. Synovial MSCs injected into the knee adhered around the meniscal defect, and promoted meniscal regeneration in rabbits. PMID: 23595964 [PubMed - indexed for MEDLINE]
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Related Articles Treatment of articular cartilage defects of the knee. Br J Hosp Med (Lond). 2013 Mar;74(3):132-7 Authors: Eldean Giebaly D, Twaij H, Ibrahim M, Haddad F PMID: 23665781 [PubMed - indexed for MEDLINE]
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Related Articles An arthroscopic approach for the treatment of osteochondral focal defects with cell-free and cell-loaded PLGA scaffolds in sheep. Cytotechnology. 2014 Mar;66(2):345-54 Authors: Fonseca C, Caminal M, Peris D, Barrachina J, Fàbregas PJ, Garcia F, Cairó JJ, Gòdia F, Pla A, Vives J Abstract Osteochondral injuries are common in humans and are relatively difficult to manage with current treatment options. The combination of novel biomaterials and expanded progenitor or stem cells provides a source of therapeutic and immunologically compatible medicines that can be used in regenerative medicine. However, such new medicinal products need to be tested in translational animal models using the intended route of administration in humans and the intended delivery device. In this study, we evaluated the feasibility of an arthroscopic approach for the implantation of biocompatible copolymeric poly-D,L-lactide-co-glycolide (PLGA) scaffolds in an ovine preclinical model of knee osteochondral defects. Moreover this procedure was further tested using ex vivo expanded autologous chondrocytes derived from cartilaginous tissue, which were loaded in PLGA scaffolds and their potential to generate hyaline cartilage was evaluated. All scaffolds were successfully implanted arthroscopically and the clinical evolution of the animals was followed by non invasive MRI techniques, similar to the standard in human clinical practice. No clinical complications occurred after the transplantation procedures in any of the animals. Interestingly, the macroscopic evaluation demonstrated significant improvement after treatment with scaffolds loaded with cells compared to untreated controls. PMID: 23673652 [PubMed]
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Related Articles A silk fibroin/chitosan scaffold in combination with bone marrow-derived mesenchymal stem cells to repair cartilage defects in the rabbit knee. J Mater Sci Mater Med. 2013 Aug;24(8):2037-46 Authors: Deng J, She R, Huang W, Dong Z, Mo G, Liu B Abstract Bone marrow-derived mesenchymal stem cells (BMSCs) were seeded in a three-dimensional scaffold of silk fibroin (SF) and chitosan (CS) to repair cartilage defects in the rabbit knee. Totally 54 rabbits were randomly assigned to BMSCs + SF/CS scaffold, SF/CS scaffold and control groups. A cylindrical defect was created at the patellofemoral facet of the right knee of each rabbit and repaired by scaffold respectively. Samples were prepared at 4, 8 and 12 weeks post-surgery for gross observation, hematoxylin-eosin and toluidine blue staining, type II collagen immunohistochemistry, Wakitani histology. The results showed that differentiated BMSCs proliferated well in the scaffold. In the BMSCs + SF/CS scaffold group, the bone defect was nearly repaired, the scaffold was absorbed and immunohistochemistry was positive. In the SF/CS scaffold alone group, fiber-like tissues were observed, the scaffold was nearly degraded and immunohistochemistry was weakly positive. In the control group, the defect was not well repaired and positive immunoreactions were not detected. Modified Wakitani scores were superior in the BMSCs + SF/CS scaffold group compared with those in other groups at 4, 8 and 12 weeks (P < 0.05). A SF/CS scaffold can serve as carrier for stem cells to repair cartilage defects and may be used for cartilage tissue engineering. PMID: 23677433 [PubMed - indexed for MEDLINE]
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Related Articles The promotion of osteochondral repair by combined intra-articular injection of parathyroid hormone-related protein and implantation of a bi-layer collagen-silk scaffold. Biomaterials. 2013 Aug;34(25):6046-57 Authors: Zhang W, Chen J, Tao J, Hu C, Chen L, Zhao H, Xu G, Heng BC, Ouyang HW Abstract The repair of osteochondral defects can be enhanced with scaffolds but is often accompanied with undesirable terminal differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Parathyroid hormone-related protein (PTHrP) has been shown to inhibit aberrant differentiation, but administration at inappropriate time points would have adverse effects on chondrogenesis. This study aims to develop an effective tissue engineering strategy by combining PTHrP and collagen-silk scaffold for osteochondral defect repair. The underlying mechanisms of the synergistic effect of combining PTHrP administration with collagen-silk scaffold implantation for rabbit knee joint osteochondral defect repair were investigated. In vitro studies showed that PTHrP treatment significantly reduced Alizarin Red staining and expression of terminal differentiation-related markers. This is achieved in part through blocking activation of the canonical Wnt/β-catenin signaling pathway. For the in vivo repair study, intra-articular injection of PTHrP was carried out at three different time windows (4-6, 7-9 and 10-12 weeks) together with implantation of a bi-layer collagen-silk scaffold. Defects treated with PTHrP at the 4-6 weeks time window exhibited better regeneration (reconstitution of cartilage and subchondral bone) with minimal terminal differentiation (hypertrophy, ossification and matrix degradation), as well as enhanced chondrogenesis (cell shape, Col2 and GAG accumulation) compared with treatment at other time windows. Furthermore, the timing of PTHrP administration also influenced PTHrP receptor expression, thus affecting the treatment outcome. Our results demonstrated that intra-articular injection of PTHrP at 4-6 weeks post-injury together with collagen-silk scaffold implantation is an effective strategy for inhibiting terminal differentiation and enhancing chondrogenesis, thus improving cartilage repair and regeneration in a rabbit model. PMID: 23702148 [PubMed - indexed for MEDLINE]
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Related Articles In vitro release and expansion of mesenchymal stem cells by a hyaluronic acid scaffold used in combination with bone marrow. Muscles Ligaments Tendons J. 2012 Oct;2(4):289-94 Authors: Spoliti M, Iudicone P, Leone R, De Rosa A, Rossetti FR, Pierelli L Abstract Articular cartilage injuries of the knee are difficult to treat due to the poor healing ability of cartilage and conventional treatment methods often give unsatisfactory results. Mesenchymal Stem Cells (MSCs) have generated interest as an alternative source of cells for cartilage tissue engineering due to their chondrogenic potential and their easy isolation from bone marrow. It has been reported that the use of scaffold in cartilage engineering acts as a support for cell adhesion, keeping the cells in the cartilage defects and therefore facilitating tissue formation, and that Hyaluronic acid (HA) is a molecule of particular interest for producing scaffold for tissue engineering. In this study we evaluated the in vitro selection and expansion of Bone Marrow MSCs (BM-MSCs) and by residual BM+HA membrane (BM-HA-MSCs) used as scaffold. Sixty mL of BM have been aspirated by the posterior iliac crest and HA membrane (Hyalograft-C, Fidia Advanced Biopolimers) was used as scaffold. BM-MSCs were cultured with D-MEM supplemented with Desamethasone, Ascorbic Acid, β-Transforming Growth Factor and Insulin. When cultured in chondrogenic selective medium MSCs from both BM and HA membrane were able to differentiate into chondrogenesis, but BM-HA-MSCs showed a higher staining intensity than BM-MSCs when they were stained with Toluidine blue. The interaction of MSCs with the HA-scaffold seems to promote by itself chondrogenesis. PMID: 23738312 [PubMed]
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Related Articles Operative treatment of osteochondral lesions of the talus. J Bone Joint Surg Am. 2013 Jun 5;95(11):1045-54 Authors: Murawski CD, Kennedy JG Abstract ➤ Osteochondral lesions of the talus are common injuries in recreational and professional athletes, with up to 50% of acute ankle sprains and fractures developing some form of chondral injury. Surgical treatment paradigms aim to restore the articular surface with a repair tissue similar to native cartilage and to provide long-term symptomatic relief.➤ Arthroscopic bone-marrow stimulation techniques, such as microfracture and drilling, perforate the subchondral plate with multiple openings to recruit mesenchymal stem cells from the underlying bone marrow to stimulate the differentiation of fibrocartilaginous repair tissue in the defect site. The ability of fibrocartilage to withstand mechanical loading and protect the subchondral bone over time is a concern.➤ Autologous osteochondral transplantation techniques replace the defect with a tubular unit of viable hyaline cartilage and bone from a donor site in the ipsilateral knee. In rare cases, a graft can also be harvested from the ipsilateral talus or contralateral knee. The limitations of donor site morbidity and the potential need for an osteotomy about the ankle should be considered. Some anterior or far posterior talar lesions can be accessed without arthrotomy or with a plafondplasty.➤ Osteochondral allograft transplantation allows an osteochondral lesion with a large surface area to be replaced with a single unit of viable articular cartilage and subchondral bone from a donor that is matched to size, shape, and surface curvature. The best available evidence suggests that this procedure should be limited to large-volume cystic lesions or salvage procedures.➤ Autologous chondrocyte implantation techniques require a two-stage procedure, the first for chondrocyte harvest and the second for implantation in a periosteum-covered or matrix-induced form after in vivo culture expansion. Theoretically, the transplantation of chondrocyte-like cells into the defect will result in hyaline-like repair tissue. PMID: 23780543 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells and cartilage lesions. Knee Surg Sports Traumatol Arthrosc. 2013 Aug;21(8):1715-6 Authors: Karlsson J PMID: 23801429 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell therapy for knee ligament, articular cartilage and meniscal injuries. Curr Stem Cell Res Ther. 2013 Nov;8(6):422-8 Authors: Ong E, Chimutengwende-Gordon M, Khan W Abstract Knee injuries involving ligament, articular cartilage and meniscus are common. The capacity for regeneration and repair of these tissues is limited due to their poor vascularity. Autologous or allogeneic stem cell transplantation has the potential to stimulate healing of these tissues. A number of preclinical studies of stem cell therapy for repair of these injuries have produced promising results. Further clinical trials are needed to test the efficacy of this technique. This paper reviews the development strategies, advances and clinical applications of stem cell therapies that are applicable to knee ligament, articular cartilage and meniscal injuries. PMID: 24016325 [PubMed - in process]
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Related Articles Management of disorders of the rotator cuff: proceedings of the ISAKOS upper extremity committee consensus meeting. Arthroscopy. 2013 Nov;29(11):1840-50 Authors: Arce G, Bak K, Bain G, Calvo E, Ejnisman B, Di Giacomo G, Gutierrez V, Guttmann D, Itoi E, Ben Kibler W, Ludvigsen T, Mazzocca A, de Castro Pochini A, Savoie F, Sugaya H, Uribe J, Vergara F, Willems J, Yoo YS, McNeil JW, Provencher MT Abstract The goal of this article is to consolidate the International Society of Arthroscopy, Knee Surgery & Orthopaedic Sports Medicine (ISAKOS) Upper Extremity Committee's (UEC's) current knowledge on rotator cuff disease and management, as well as highlight key unresolved issues. The rotator cuff is an anatomically complex structure important for providing glenohumeral function and stability as part of a closed chain system. Current consensus suggests rotator cuff injuries are most accurately diagnosed, at levels similar to diagnosis by magnetic resonance imaging, with a combination of cuff- and impingement-specific clinical tests. Updates in the understanding of acromion morphology, the insertional anatomy of the rotator cuff, and the role of suprascapular nerve release may require changes to current classification systems and surgical strategies. Although initial management focuses on nonoperative protocols, discussion continues on whether surgery for isolated impingement is clinically more beneficial than rehabilitation. However, clear indications have yet to be established for the use of single- versus double-row repair because evidence confirms neither is clinically efficacious than the other. Biceps tenodesis, however, in non-isolated cuff tears has proven more successful in addressing the etiology of shoulder pain and yields improved outcomes over tenotomy. Data reviewing the benefits of tendon transfers, shoulder prostheses, and mechanical scaffolds, as well as new research on the potential benefit of platelet-rich plasma, pluripotential stem cells, and gene therapies, will also be presented. PMID: 24041864 [PubMed - indexed for MEDLINE]
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Related Articles PVA-chitosan composite hydrogel versus alginate beads as a potential mesenchymal stem cell carrier for the treatment of focal cartilage defects. Knee Surg Sports Traumatol Arthrosc. 2013 Oct 22; Authors: Dashtdar H, Murali MR, Abbas AA, Suhaeb AM, Selvaratnam L, Tay LX, Kamarul T Abstract PURPOSE: To investigate whether mesenchymal stem cells (MSCs) seeded in novel polyvinyl alcohol (PVA)-chitosan composite hydrogel can provide comparable or even further improve cartilage repair outcomes as compared to previously established alginate-transplanted models. METHODS: Medial femoral condyle defect was created in both knees of twenty-four mature New Zealand white rabbits, and the animals were divided into four groups containing six animals each. After 3 weeks, the right knees were transplanted with PVA-chitosan-MSC, PVA-chitosan scaffold alone, alginate-MSC construct or alginate alone. The left knee was kept as untreated control. Animals were killed at the end of 6 months after transplantation, and the cartilage repair was assessed through Brittberg morphological score, histological grading by O'Driscoll score and quantitative glycosaminoglycan analysis. RESULTS: Morphological and histological analyses showed significant (p < 0.05) tissue repair when treated with PVA-chitosan-MSC or alginate MSC as compared to the scaffold only and untreated control. In addition, safranin O staining and the glycosaminoglycan (GAG) content were significantly higher (p < 0.05) in MSC treatment groups than in scaffold-only or untreated control group. No significant difference was observed between the PVA-chitosan-MSC- and alginate-MSC-treated groups. CONCLUSION: PVA-chitosan hydrogel seeded with mesenchymal stem cells provides comparable treatment outcomes to that of previously established alginate-MSC construct implantation. This study supports the potential use of PVA-chitosan hydrogel seeded with MSCs for clinical use in cartilage repair such as traumatic injuries. PMID: 24146054 [PubMed - as supplied by publisher]
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Related Articles [Articular cartilage regenerative therapy with synovial mesenchymal stem cells in a pig model]. Clin Calcium. 2013 Dec;23(12):1741-9 Authors: Nakamura T, Sekiya I, Muneta T, Kobayashi E Abstract Current therapies for cartilage injury remain some issues such as the quality of regenerated cartilage and its invasiveness. We have been trying to develop a low invasive treatment for cartilage regeneration with synovial mesenchymal stem cells (MSCs) . Here we introduce our preclinical study with miniature pigs whose knee joints are similar to those of humans in terms of size and cartilage metabolism. Cartilage defect was created at the weight bearing area of both porcine knee joints. Synovial MSCs were transplanted by delivering a synovial MSC suspension onto the cartilage defect of the one side and the knee was kept immobilized for 10 minutes. Sequential arthroscopic and histological observations showed the contribution of synovial MSCs after transplantation, and a better hyaline cartilaginous-tissue regeneration in the MSC-treated knees than in the non-treated control knees at 12 weeks. Based on this and other preclinical studies, we have started a clinical study for cartilage regeneration with autologous synovial MSCs. PMID: 24292528 [PubMed - indexed for MEDLINE]
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Related Articles Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2013 Dec 11; Authors: Koh YG, Choi YJ, Kwon SK, Kim YS, Yeo JE Abstract PURPOSE: In the present study, the clinical outcomes and second-look arthroscopic findings of intra-articular injection of stem cells with arthroscopic lavage for treatment of elderly patients with knee osteoarthritis (OA) were evaluated. METHODS: Stem cell injections combined with arthroscopic lavage were administered to 30 elderly patients (≥65 years) with knee OA. Subcutaneous adipose tissue was harvested from both buttocks by liposuction. After stromal vascular fractions were isolated, a mean of 4.04 × 10(6) stem cells (9.7 % of 4.16 × 10(7) stromal vascular fraction cells) were prepared and injected in the selected knees of patients after arthroscopic lavage. Outcome measures included the Knee Injury and Osteoarthritis Outcome Scores, visual analog scale, and Lysholm score at preoperative and 3-, 12-, and 2-year follow-up visits. Sixteen patients underwent second-look arthroscopy. RESULTS: Almost all patients showed significant improvement in all clinical outcomes at the final follow-up examination. All clinical results significantly improved at 2-year follow-up compared to 12-month follow-up (P < 0.05). Among elderly patients aged >65 years, only five patients demonstrated worsening of Kellgren-Lawrence grade. On second-look arthroscopy, 87.5 % of elderly patients (14/16) improved or maintained cartilage status at least 2 years postoperatively. Moreover, none of the patients underwent total knee arthroplasty during this 2-year period. CONCLUSION: Adipose-derived stem cell therapy for elderly patients with knee OA was effective in cartilage healing, reducing pain, and improving function. Therefore, adipose-derived stem cell treatment appears to be a good option for OA treatment in elderly patients. LEVEL OF EVIDENCE: Therapeutic case series study, Level IV. PMID: 24326779 [PubMed - as supplied by publisher]
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Related Articles [Medium- to long-term follow-up after anterior cruciate ligament rupture and repair in healing response technique]. Z Orthop Unfall. 2013 Dec;151(6):570-9 Authors: Jorjani J, Altmann D, Auen R, Koopmann C, Lyutenski B, Wirtz DC Abstract BACKGROUND: Healing response (HR) is an all-arthroscopic technique for treatment of acute proximal anterior cruciate ligament (ACL) tears within 6 weeks after injury. By means of arthroscopically controlled microfracture holes in the native femoral attachment and perforations of the ACL itself the exit of stem cells and growth factors is induced and the ligament can heal into its native attachment zone. The purpose of the study was to document medium- to long-term results after 5 years or longer following the healing response (HR) procedure. The aim of our study was to show that HR is a treatment option for acute proximal ACL tears. MATERIAL AND METHODS: Between 2004 and 2007 126 patients were treated in healing response technique in our hospital. Patients with a complete proximal ACL tear and operation within 6 weeks of initial injury were included in this study. Patients who had complex knee injuries with multidirectional instability, ACL rerupture, contralateral ACL reconstruction, contralateral ACL rupture or knee replacement and cartilage repair procedures (AMIC, MACT, OATS) were excluded. 43 (23 women/20 men; mean age at time of surgery 36.6 years ± 11.6; range: 16 to 66 years) of 89 eligible patients received clinical follow-up up to 8 years after surgery (mean: 6.3 years). Lysholm score, Tegner activity score, a modified IKDC-2000 knee examination form and an individually created questionnaire were used for evaluation. Furthermore, range of motion, muscle circumference of the lower limb and the anterior tibial translation were measured with a KT-1000 arthrometer™ (MEDmetric® Corporation, San Diego, USA). RESULTS: 15.1 % of all patients showed a primary insufficiency after HR. 24.6 % of the 126 patients required subsequent ACL reconstruction up to the time of data collection. The 43 patients who received clinical follow-up showed a mean Lysholm score of 92 ± 8.9 points. 72 % reached their original level of activity in the Tegner activity score. According to the IKDC evaluation system 90.7 % of all patients were grade A. 93 % did not show muscles atrophies of the lower limb. There were no limitations in range of motion. Mean side-to-side difference in the KT-1000 manual-maximum displacement test measurements was 1.3 mm ± 1.6 mm. 97.7 % patients had a normal or nearly normal knee function and 86 % rated the overall treatment as good to very good. CONCLUSION: Patients with good clinical results 6 to 12 weeks after HR show even in the medium- to long-term follow-up good clinical outcomes as well as objective stability. In selected cases HR is an alternative treatment option for acute, proximal ACL ruptures. When indicating an HR procedure, it should be taken into consideration that up to 15 % of all patients could have a primary insufficiency. PMID: 24347411 [PubMed - in process]
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Related Articles One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. Am J Sports Med. 2014 Mar;42(3):648-57 Authors: Gobbi A, Karnatzikos G, Sankineani SR Abstract BACKGROUND: Chondral lesions in athletically active patients cause considerable morbidity, and treatment with existing cell-based therapies can be challenging. Bone marrow has been shown as a possible source of multipotent stem cells (MSCs) with chondrogenic potential and is easy to harvest during the same surgical procedure. PURPOSE: To investigate the clinical outcome in a group of active patients with large full-thickness chondral defects of the knee treated with 1-step surgery using bone marrow-derived MSCs and a second-generation matrix. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From January 2007 to February 2010, 25 patients (average age, 46.5 years) with symptomatic large chondral defects of the knee (International Cartilage Repair Society grade 4) who underwent cartilage transplantation with MSCs and a collagen type I/III matrix were followed up for a minimum of 3 years. The average lesion size was 8.3 cm(2). Coexisting injuries were treated during the same surgical procedure in 18 patients. All patients underwent a standard postoperative rehabilitation program. Preoperative and postoperative evaluations at 1-year, 2-year, and final follow-up included radiographs, magnetic resonance imaging (MRI), and visual analog scale (VAS) for pain, International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm, Marx, and Tegner scores. Seven patients underwent second-look arthroscopic surgery, with 4 consenting to a tissue biopsy. RESULTS: No patients were lost at final follow-up. The average preoperative values for the evaluated scores were significantly improved at final follow-up (P < .001): VAS, 5.4 ± 0.37 to 0.48 ± 0.19; IKDC subjective, 37.92 ± 4.52 to 81.73 ± 2.42; KOOS pain, 61.04 ± 3.95 to 93.32 ± 1.92; KOOS symptoms, 55.64 ± 3.23 to 89.32 ± 2.32; KOOS activities of daily living, 63.96 ± 4.48 to 91.20 ± 2.74; KOOS sports, 34.20 ± 5.04 to 80.00 ± 3.92; KOOS quality of life, 32.20 ± 4.43 to 83.04 ± 3.37; Lysholm, 46.36 ± 2.25 to 86.52 ± 2.73; Marx, 3.00 ± 0.79 to 9.04 ± 0.79; and Tegner, 2.12 ± 0.32 to 5.64 ± 0.26. Patients younger than 45 years of age and those with smaller or single lesions showed better outcomes. The MRI scans showed good stability of the implant and complete filling of the defect in 80% of patients, and hyaline-like cartilage was found in the histological analysis of the biopsied tissue. No adverse reactions or postoperative complications were noted. CONCLUSION: The treatment of large chondral defects with MSCs is an effective procedure and can be performed routinely in clinical practice. Moreover, it can be achieved with 1-step surgery, avoiding a previous surgical procedure to harvest cartilage and subsequent chondrocyte cultivation. PMID: 24458240 [PubMed - in process]
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Related Articles Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. J Am Acad Orthop Surg. 2014 Feb;22(2):68-79 Authors: Anz AW, Hackel JG, Nilssen EC, Andrews JR Abstract Advances in our knowledge of cell signaling and biology have led to the development of products that may guide the healing/regenerative process. Therapies are emerging that involve growth factors, blood-derived products, marrow-derived products, and stem cells. Animal studies suggest that genetic modification of stem cells will be necessary; studies of cartilage and meniscus regeneration indicate that immature cells are effective and that scaffolds are not always necessary. Current preclinical animal and clinical human data and regulatory requirements are important to understand in light of public interest in these products. PMID: 24486753 [PubMed - indexed for MEDLINE]
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