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1.  Establishing proof of concept: Platelet-rich plasma and bone marrow aspirate concentrate may improve cartilage repair following surgical treatment for osteochondral lesions of the talus 
World Journal of Orthopedics  2012;3(7):101-108.
Osteochondral lesions of the talus are common injuries in the athletic patient. They present a challenging clinical problem as cartilage has a poor potential for healing. Current surgical treatments consist of reparative (microfracture) or replacement (autologous osteochondral graft) strategies and demonstrate good clinical outcomes at the short and medium term follow-up. Radiological findings and second-look arthroscopy however, indicate possible poor cartilage repair with evidence of fibrous infill and fissuring of the regenerative tissue following microfracture. Longer-term follow-up echoes these findings as it demonstrates a decline in clinical outcome. The nature of the cartilage repair that occurs for an osteochondral graft to become integrated with the native surround tissue is also of concern. Studies have shown evidence of poor cartilage integration, with chondrocyte death at the periphery of the graft, possibly causing cyst formation due to synovial fluid ingress. Biological adjuncts, in the form of platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), have been investigated with regard to their potential in improving cartilage repair in both in vitro and in vitro settings. The in vitro literature indicates that these biological adjuncts may increase chondrocyte proliferation as well as synthetic capability, while limiting the catabolic effects of an inflammatory joint environment. These findings have been extrapolated to in vitro animal models, with results showing that both PRP and BMAC improve cartilage repair. The basic science literature therefore establishes the proof of concept that biological adjuncts may improve cartilage repair when used in conjunction with reparative and replacement treatment strategies for osteochondral lesions of the talus.
PMCID: PMC3399015  PMID: 22816065
Osteochondral lesion; Cartilage repair; Platelet-rich plasma; Bone marrow aspirate concentrate
2.  The Clinical Use of Human Culture–Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects: A Pilot Study and Preliminary Results 
Cartilage  2010;1(4):253-261.
To test the hypothesis that platelet-rich fibrin glue (PR-FG) can be used clinically as a scaffold to deliver autologous culture-expanded bone marrow mesenchymal stem cells (BM-MSCs) for cartilage repair and to report clinical results 1 y after implantation of MSCs PR-FG.
Patients and Methods
Autologous BM-MSCs were culture expanded, placed on PR-FG intraoperatively, and then transplanted into 5 full-thickness cartilage defects of femoral condyles of 5 patients and covered with an autologous periosteal flap. Patients were evaluated clinically at 6 and 12 mo by the Lysholm and Revised Hospital for Special Surgery Knee (RHSSK) scores and radiographically by x-rays and magnetic resonance imaging (MRI) at the same time points. Repair tissue in 2 patients was rated arthroscopically after 12 mo using the International Cartilage Repair Society (ICRS) Arthroscopic Score.
Study Design
Case series; level of evidence 4.
All patients’ symptoms improved over the follow-up period of 12 mo. Average Lysholm and RHSSK scores for all patients showed statistically significant improvement at 6 and 12 mo postoperatively (P < 0.05). There was no statistically significant difference between the 6 and 12 mo postoperative clinical scores (P = 0.18). ICRS arthroscopic scores were 8/12 and 11/12 (nearly normal) for the 2 patients who consented to arthroscopy. MRI of 3 patients at 12 mo postoperatively revealed complete defect fill and complete surface congruity with native cartilage, whereas that of 2 patients showed incomplete congruity.
Autologous BM-MSC transplantation on PR-FG as a cell scaffold may be an effective approach to promote the repair of articular cartilage defects of the knee in human patients.
PMCID: PMC3002255  PMID: 21170288
mesenchymal stem cells; platelet-rich plasma; fibrin glue; cartilage; repair
3.  Serum CTXii Correlates With Articular Cartilage Degeneration After Anterior Cruciate Ligament Transection or Arthrotomy Followed by Standardized Exercise 
Sports Health  2012;4(6):510-517.
Anterior cruciate ligament injury increases risk for accelerated development of osteoarthritis. The effect of exercise on articular cartilage following joint injury is not well understood. Biochemical biomarkers of collagen degradation and proteoglycan turnover are potential indicators for early articular cartilage degeneration.
This study tests the hypothesis that serum concentrations of CS846 and CTXii correlate with structural changes to articular cartilage following joint injury in exercised animals.
Study Design:
Controlled laboratory study.
Twenty-four Sprague-Dawley rats underwent either arthrotomy alone (sham surgery) or anterior cruciate ligament transection (ACLT). Animals were recovered for 3 weeks and then exercised on a treadmill at 18 m per minute, 1 hour per day, 5 days per week, until sacrifice either 6 or 12 weeks later. Articular cartilage was assessed grossly, and histology was graded using modified Mankin, toluidine blue, and modified David-Vaudey scales. Serum collected preoperatively and at sacrifice was assayed by ELISA for CTXii and CS846.
At 6 weeks, gross grades (P < 0.01), modified Mankin scores (P < 0.03), and toluidine blue scores (P < 0.04) were higher, reflecting increased degeneration in ACLT animals compared with sham surgery animals. Serum CS846 increased after 6 weeks in ACLT animals (P < 0.05). Serum CTXii levels strongly correlated with Mankin degenerative scores (coefficient = 0.81, P < 0.01) and David-Vaudey histology grades (coefficient = 0.73, P < 0.01) at 6 weeks. While gross grades remained higher at 12 weeks in ACLT animals (P < 0.04), no differences were seen in serum CS846 and CTXii. Histology scores also showed no differences between ACLT and sham due to increasing degeneration in the sham surgery group.
The strong correlation between serum CTXii and microstructural changes to articular cartilage following joint injury demonstrates potential use of serum biomarkers for early detection of cartilage degeneration. Increasing cartilage degeneration in exercised sham-surgery animals suggests that early loading may have negative effects on articular cartilage due to either mechanical injury or hemarthrosis after arthrotomy.
Clinical Relevance:
Patients with anterior cruciate ligament injury are at increased risk for development of posttraumatic osteoarthritis. CTXii may be useful for early detection of joint degeneration. Further study on the effects of exercise after injury is important to postinjury and postoperative rehabilitation.
PMCID: PMC3497947  PMID: 24179591
serum CTXii; serum CS846; biochemical biomarkers; anterior cruciate ligament transection; articular cartilage; hemarthrosis; rat
4.  Single Intra-Articular Injection of Adeno-Associated Virus Results in Stable and Controllable In vivo Transgene Expression in Normal Rat Knees 
To test the hypothesis that in vivo transgene expression mediated by single intra-articular injection of adeno-associated virus serotype 2 (AAV2) persists within intra-articular tissues 1-year post-injection and can be externally controlled using an AAV2-based tetracycline-inducible gene regulation system containing the tetracycline response element (TRE) promoter.
Sprague-Dawley rats received intra-articular injections of AAV2-CMV-GFP and AAV2-CMV-Luc into their right and left knees, respectively. Luciferase expression was evaluated over 1-year using bioluminescence imaging. After sacrifice, tissues were analyzed for GFP+ cells by fluorescent microscopy. To study external control of intra-articular AAV-transgene expression, another set of rats were co-injected with AAV2-TRE-Luc and AAV2-CMV-reverse-tetracycline-controlled transactivator (rtTA) into the right knees, and AAV2-CMV-Luc and AAV2-CMV-rtTA into the left knees. Rats received oral doxycycline (Dox), an analogue of tetracycline, for 7 days. Luciferase expression was assessed by bioluminescence imaging.
Luciferase expression was localized to the injected joint and persisted throughout the 1-year study period. Abundant GFP+ cells were observed within intra-articular soft tissues. Transgene expression in AAV2-TRE-Luc injected joints was upregulated by oral administration of Dox, and downregulated following its removal, at 14-days and 13-months post-AAV injection.
This longitudinal in vivo study shows that sustained and stable AAV-mediated intra-articular transgene expression can be achieved through a single intra-articular injection and can be controlled using a tetracycline-controlled inducible AAV system in a normal rat knee model. Highly regulatable long-term intra-articular transgene expression is of potential clinical utility for development of treatment strategies for chronic intra-articular disease processes such as inflammatory and degenerative arthritis.
PMCID: PMC3139006  PMID: 21571082
adeno-associated virus; gene therapy; cartilage; injection; doxycycline
5.  Release of Bioactive Adeno-Associated Virus from Fibrin Scaffolds: Effects of Fibrin Glue Concentrations 
Tissue Engineering. Part A  2011;17(15-16):1969-1978.
Fibrin glue (FG) is used in a variety of clinical applications and in the laboratory for localized and sustained release of factors potentially important for tissue engineering. However, the effect of different fibrinogen concentrations on FG scaffold delivery of bioactive adeno-associated viruses (AAVs) has not been established. This study was performed to test the hypothesis that FG concentration alters AAV release profiles, which affect AAV bioavailability. Gene transfer efficiency of AAV-GFP released from FG was measured using HEK-293 cells. Bioactivity of AAV transforming growth factor-beta1 (TGF-β1) released from FG was assessed using the mink lung cell assay, and by measuring induction of cartilage-specific gene expression in human mesenchymal stem cells (hMSCs). Nondiluted FG had longer clotting times, smaller pore sizes, thicker fibers, and slower dissolution rate, resulting in reduced release of AAV. AAV release and gene transfer efficiency was higher with 25% and 50% FG than with the 75% and 100% FG. AAV-TGF-β1 released from dilute-FG transduced hMSCs, resulting in higher concentrations of bioactive TGF-β1 and greater upregulation of cartilage-specific gene expression compared with hMSC from undiluted FG. This study, showing improved release, transduction efficiency, and chondrogenic effect on hMSC of bioactive AAV-TGF-β1 released from diluted FG, provides information important to optimization of this clinically available scaffold for therapeutic gene delivery, both in cartilage regeneration and for other tissue engineering applications.
PMCID: PMC3142631  PMID: 21449684

Results 1-5 (5)