Patrick Vavken

Platelet Activation by Collagen Provides Sustained Release of Anabolic Cytokines

Background: Platelet-rich plasma (PRP) has been increasingly used in sports medicine applications. Platelets are thought to release growth factors important in wound healing, including transforming growth factor (TGF-β1), platelet-derived growth factor (PDGF-AB), and vascular endothelial growth factor (VEGF). However, little is known about the effect of platelet activator choice on growth factor release kinetics. Hypothesis: The choice of platelet activator would affect the timing and level of growth factor release from PRP. Study Design: Controlled laboratory study. Methods: Platelet-rich plasma aliquots were activated with either thrombin or collagen. A control group of whole blood aliquots was clotted with thrombin. Supernatant containing the released growth factors was collected daily for 1 week. Levels of TGF-β1, PDGF-AB, and VEGF were measured using enzyme-linked immunosorbent assay (ELISA). Results: The use of thrombin as an activator resulted in immediate release of TGF-β1 and PDGF-AB, while the collagen-activated PRP clots released similar amounts each day for 5 days. The use of collagen as an activator resulted in an 80% greater cumulative release of TGF-β1 from the PRP aliquots over 7 days (P < .001). Concentrating platelets to 3 times the systemic blood level resulted in a 3-fold higher release of TGF-β1, 2.5-fold greater release of PDGF, and 5-fold greater release of VEGF (all P < .0001) when compared with whole blood control clots, but no significant differences in the timing of release were noted. Conclusion: These experiments demonstrated that the choice of platelet activator can significantly influence the release kinetics of cytokines from PRP, with thrombin resulting in an immediate release and collagen having a more sustained release pattern. Clinical Relevance: The level and rate of growth factor release depends on the selected platelet activator, a factor that should be considered when selecting a PRP system for a given application.

Treating Anterior Cruciate Ligament Tears in Skeletally Immature Patients

PURPOSE To systematically review the current evidence for conservative and surgical treatment of anterior cruciate ligament (ACL) tears in skeletally immature patients. METHODS A systematic search of PubMed, CINAHL, EMBASE, CCTR, and CDSR was performed for surgical and/or conservative treatment of complete ACL tears in immature individuals. Studies with less than six months of follow-up were excluded. Study quality was assessed and data were collected on clinical outcome, growth disturbance, and secondary joint damage. RESULTS We identified 48 studies meeting the inclusion criteria. Conservative treatment was found to result in poor clinical outcomes and a high incidence of secondary defects, including meniscal and cartilage injury. Surgical treatment had only very weak evidence for growth disturbance, yet strong evidence of good postoperative stability and function. No specific surgical treatment showed clearly superior outcomes, yet the studies using physeal-sparing techniques had no reported growth disturbances at all. CONCLUSIONS The current best evidence suggests that surgical stabilization should be considered the preferred treatment in immature patients with complete ACL tears. While physeal-sparing techniques are not associated with a risk of growth disturbance, transphyseal reconstruction is an alternative with a beneficial safety profile and a minimal risk of growth disturbance. Conservative treatment commonly leads to meniscal damage and cartilage destruction and should be considered a last resort. LEVEL OF EVIDENCE Level IV, systematic review of Level II, III, and IV studies.

Biomechanical outcomes after bioenhanced anterior cruciate ligament repair and anterior cruciate ligament reconstruction are equal in a porcine model.

PURPOSE The objective of this study was to compare the biomechanical outcomes of a new method of anterior cruciate ligament (ACL) treatment, bioenhanced ACL repair, with ACL reconstruction in a large animal model. METHODS Twenty-four skeletally immature pigs underwent unilateral ACL transection and were randomly allocated to receive bioenhanced ACL repair with a collagen-platelet composite, allograft (bone-patellar tendon-bone) reconstruction, or no further treatment (n = 8 for each group). The structural properties and anteroposterior laxity of the experimental and contralateral ACL-intact knees were measured 15 weeks postoperatively. All dependent variables were normalized to those of the contralateral knee and compared by use of generalized linear mixed models. RESULTS After 15 weeks, bioenhanced ACL repair and ACL reconstruction produced superior biomechanical outcomes to ACL transection. However, there were no significant differences between bioenhanced ACL repair and ACL reconstruction for maximum load (P = .4745), maximum displacement (P = .4217), or linear stiffness (P = .6327). There were no significant differences between the 2 surgical techniques in anteroposterior laxity at 30° (P = .7947), 60° (P = .6270), or 90° (P = .9008). CONCLUSIONS Bioenhanced ACL repair produced biomechanical results that were not different from ACL reconstruction in a skeletally immature, large animal model, although the variability associated with both procedures was large. Both procedures produced significantly improved results over ACL transection, showing that both were effective treatments in this model. CLINICAL RELEVANCE Bioenhanced ACL repair may one day provide an alternative treatment option for ACL injury.

The Effect of Platelet Concentrates on Graft Maturation and Graft-Bone Interface Healing in Anterior Cruciate Ligament Reconstruction in Human Patients: A Systematic Review of Controlled Trials

PURPOSE To systematically review the current evidence for the effects of platelet concentrates on (1) graft maturation and (2) graft-bone interface healing in anterior cruciate ligament (ACL) reconstruction in human, controlled trials and for ensuing differences in clinical outcomes. METHODS A systematic search of PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was performed for controlled trials of human ACL reconstruction with and without platelet concentrates. Data validity was assessed, and data were collected on graft maturation, graft-bone interface healing, and clinical outcome. RESULTS Eight studies met the inclusion criteria. Seven studies reported on graft maturation with significantly better outcomes in the platelet groups in 4, and there were large differences in means in an additional 2 studies. Five studies reported on tunnel healing, and 4 found no difference between groups. Three studies assessed clinical outcome but found no differences, regardless of whether they had shown a beneficial effect (1 of 3) or no effect (2 of 3) of platelets on graft and tunnel healing. CONCLUSIONS The current best evidence suggests that the addition of platelet concentrates to ACL reconstruction may have a beneficial effect on graft maturation and could improve it by 20% to 30% on average, but with substantial variability. The most likely mode of action is that treatment with platelets accelerates graft repopulation and remodeling, and this interpretation is supported by the existing data and is biologically plausible. However, the current evidence also shows only a very limited influence of platelet concentrates on graft-bone interface healing and no significant difference in clinical outcomes. LEVEL OF EVIDENCE Level III, systematic review of Level I, II, and III studies.

Effectiveness of autologous chondrocyte implantation in cartilage repair of the knee: a systematic review of controlled trials.

OBJECTIVE The relative differences in effectiveness of subchondral stimulation, osteochondral grafts, and autologous chondrocyte implantation (ACI) are still unclear. It is the objective of this study to systematically review the literature on ACI compared to other treatments by clinical outcome and the quality of the repair tissue, including an assessment of the validity of these findings. METHOD The online databases PubMed, EMBASE, Cochrane Controlled Trial Register, CENTRAL, CINAHL, and BioMed were searched. Controlled trials comparing ACI with other methods of cartilage repair or placebo were included. Data on clinical outcome and the quality of the repair tissue was abstracted in duplicate. Study validity was assessed by individual components (randomization, blinded outcome assessment, sample size, attrition, percentage biopsies). RESULTS Nine studies were included. The internal validity of most of these studies was poor. Studies comparing ACI with subchondral stimulation have a higher quality and show no differences in clinical outcomes, but suggest better results in tissue quality. The high quality evidence comparing ACI with osteochondral grafts shows better clinical outcomes and higher tissue quality after ACI. CONCLUSION Among the included studies there is much inconsistency in methodological quality and findings. Regardless of these problems, the absolute differences between groups are fairly small, thus raising questions about their clinical importance. Future studies will be needed to answer the question of benefits of ACI compared to other treatments, and could profit from addressing and avoiding the problems seen in this group. Finally conclusions concerning long-term effects are still difficult.

Prophylaxis of heterotopic ossification of the hip: systematic review and meta-analysis.

Heterotopic ossification (HO) is a potentially severe, if infrequent, complication in hip surgery, and uncertainty exists regarding whether to use NSAIDs or radiation in its prevention. Thus, we systematically reviewed the literature in MedLine, EMBASE, CINAHL, and the Cochrane Controlled Trial Register and, after ruling out publication bias and data heterogeneity, performed a meta-analysis of randomized, controlled trials to assess effectiveness and complications of NSAIDs and radiation in the prevention of HO. We identified nine studies reporting on effectiveness and complications including a total of 1295 patients. The pooled risk ratio for the effectiveness in HO prevention was 0.96 (95% confidence interval, 0.88–1.06) and was independent of the type of surgery (THA or open reduction and internal fixation). There was no association with gender, age, length of followup, or year of publication. The risk ratio for associated complications was 0.79 (95% confidence interval, 0.45–1.41), and, again, was independent of the aforementioned factors. We found no evidence for a statistically significant or clinically important difference between NSAIDs or radiation in preventing HO.

TRITON‐X is most effective among three decellularization agents for ACL tissue engineering

Ruptures of the anterior cruciate ligament (ACL) are still associated with high rates of long‐term complications, even in patients undergoing modern, state‐of‐the‐art replacement. Tissue‐engineering approaches have been shown to be of value in improving treatment of ACL ruptures. However, the success of tissue‐engineering procedures depends on the choice of an appropriate biomaterial. Decellularized ACL tissue potentially combines the structural composition of the targeted tissue with a reduced risk of graft rejection or disease transmission. In this study, we tested the effectiveness of currently available decellularization methods based on TRITON‐X, sodium dodecyl sulfate (SDS), and trypsin. After identifying the most effective decellularization method, the capacity for reseeding with ACL fibroblasts was studied. All decellularization protocols reduced DNA content, with TRITON‐X treatment having the greatest effect. Concurrently, decellularization did not affect tissue collagen or total protein content, but did decrease glycosaminoglycan content. TRITON‐X also resulted the least glycosaminoglycan depletion. Porcine ACL tissue after decellularization with TRITON‐X could be successfully reseeded with human ACL fibroblasts as demonstrated by steady DNA content and increasing pro‐collagen expression.

Reduced platelet concentration does not harm PRP effectiveness for ACL repair in a porcine in vivo model.

Enhanced primary repair of the ACL using a collagen scaffold loaded with platelets has been shown to improve the functional healing of suture repair in animal models. In this study, our objectives were to determine if lowering the platelet concentration would reduce the structural properties of the repaired ACL and increase postoperative knee laxity. Eight Yucatan mini‐pigs underwent bilateral suture repair. In one knee, the repair was augmented with a collagen scaffold saturated with platelet‐rich plasma (PRP) containing five times the systemic baseline of platelets (5×) while the contralateral knee had a collagen scaffold saturated with PRP containing three times the systemic baseline of platelets (3×). After 13 weeks of healing, knee joint laxity and the structural properties of the ACL were measured. The 3× platelet concentration resulted in a 24.1% decrease in cellular density of the repair tissue (p < 0.05), but did not significantly decrease the structural properties [3× vs. 5×: 362 N vs. 291 N (p = 0.242) and 70 N/mm vs. 53 N/mm (p = 0.189) for the yield load and linear stiffness, respectively]. The 3× platelet concentration also did not significantly change the mean anteroposterior knee laxity at 30° and 90° of flexion [5× vs. 3×: 3.5 mm vs. 5.1 mm (p = 0.140), and 6.1 mm vs. 6.3 mm (p = 0.764)] but did result in a lower AP laxity at 60° [5× vs. 3×: 8.6 mm vs. 7.3 mm (p = 0.012)]. The decrease in platelet concentration from 5× to 3× to enhance suture repair of the ACL did not significantly harm the mechanical outcomes in this animal model.

Effectiveness of pulsed electromagnetic field therapy in the management of osteoarthritis of the knee: a meta-analysis of randomized controlled trials

OBJECTIVE To assess the effectiveness of pulsed electromagnetic fields compared with placebo in the management of osteoarthritis of the knee. DATA SOURCES A systematic review of PubMed, EMBASE, and the Cochrane Controlled Trials Register. METHODS Randomized, controlled trials reporting on the blinded comparison of pulsed electromagnetic fields with placebo were included. Validity was tested according to the Jadad Scale. Studies were pooled using fixed-effects and random-effects models after exclusion of publication bias and assessment of heterogeneity. Sensitivity analyses and meta-regression were performed to test the stability of our findings. RESULTS Nine studies, including 483 patients, were pooled. No significant difference could be shown for pain (weighted mean difference 0.2 patients; 95% confidence interval (CI): -0.4 to 0.8) or stiffness (weighted mean difference 0.3; 95% CI: -0.3 to 0.9). There was a significant effect on activities of daily living (weighted mean difference 0.8; 95% CI 0.2-1.4, p = 0.014) and scores (standardized mean difference 0.4; 95% CI: 0.05-0.8, p = 0.029). We saw only statistically insignificant differences between studies with different treatment protocols. CONCLUSION Pulsed electromagnetic fields improve clinical scores and function in patients with osteoarthritis of the knee and should be considered as adjuvant therapies in their management. There is still equipoise of evidence for an effect on pain in the current literature.

The potential for primary repair of the ACL

The objective of this work is to assess the feasibility of successfully repairing the torn anterior cruciate ligament (ACL). Two major motivators for developing a new treatment for ACL injuries are the recently reported high rates of osteoarthritis, after conventional ACL reconstruction, and the problem of how to safely treat skeletally immature patients. A key factor in developing such a technique was the identification of the main inhibitor of intrinsic ACL healing—the lack of clot formation between the 2 torn ends of the ligament. A bioactive and biocompatible scaffold, which could be placed in the wound site to enhance cellular proliferation and biosynthesis, was developed. This biomaterial has shown promising functional outcomes in several large animal models of primary repair of partial and complete ACL transection over 4 to 14 weeks, suggesting potential for a successful, future clinical application.