Cassandra A. Lee

Clinical Results of Arthroscopic Single-Bundle Transtibial Posterior Cruciate Ligament Reconstruction A Systematic Review

Background: Reconstruction of the posterior cruciate ligament has traditionally been performed using an arthroscopically assisted single-bundle transtibial technique. Unfortunately, clinical studies evaluating this procedure are rare. In addition, there are no pooled analyses evaluating the effectiveness of this procedure for isolated posterior cruciate ligament tears. Hypothesis: Patients who undergo arthroscopically assisted, single-bundle, transtibial posterior cruciate ligament reconstruction will exhibit subjective improvement in knee function despite persistent objective knee laxity. Study Design: Systematic review. Methods: A structured literature search was performed to identify those clinical studies assessing the results of an arthroscopically assisted single-bundle transtibial posterior cruciate ligament reconstruction for isolated posterior cruciate ligament tears. The published data meeting the inclusion criteria were systematically reviewed with an emphasis on residual posterior laxity, subjective and objective functional outcome, activity level, patient satisfaction, incidence of osteoarthritis, and postoperative complications. Results: A total of 10 studies were identified that met the inclusion criteria. Mean postoperative instrumented posterior knee laxity varied from 1.96 mm to 5.90 mm, which was considerably improved from preoperative values (range, 8.38-12.3 mm). The range of mean values of the Lysholm knee scores was 81 to 100 points. The overall International Knee Documentation Committee rating was categorized as “normal” or “nearly normal” in 75% of patients and the mean Tegner activity score varied from 4.7 to 6.3 points. Degenerative osteoarthritis was frequently noted at the time of the most recent follow-up. There were few complications reported. Conclusion: Arthroscopically assisted single-bundle transtibial posterior cruciate ligament reconstruction for isolated posterior cruciate ligament tears can improve posterior knee laxity by 1 grade, although this procedure does not reliably restore normal knee stability. Return to recreational and athletic activity was predictable, with 75% of patients exhibiting a normal or nearly normal objective outcome, although degenerative osteoarthritis was not prevented by this procedure.

Musculoskeletal changes following non-invasive knee injury using a novel mouse model of post-traumatic osteoarthritis

OBJECTIVE Post-traumatic osteoarthritis (PTOA) is a common consequence of traumatic joint injury, with 50% of anterior cruciate ligament (ACL) rupture patients developing PTOA within 10-20 years. Currently accepted mouse models of PTOA initiate symptoms using various methods, none of which faithfully mimic clinically-relevant injury conditions. In this study we characterize a novel non-invasive mouse model of PTOA that injures the ACL with a single load of tibial compression overload. We utilize this model to determine the time course of articular cartilage and subchondral bone changes following knee injury. DESIGN Mice were euthanized 1, 3, 7, 14, 28, or 56 days after non-invasive knee injury. Knees were scanned using micro-computed tomography (μCT) in order to quantify subchondral trabecular bone, subchondral bone plate, and non-native bone formation (heterotopic ossification). Development of osteoarthritis (OA) was graded using the osteoarthritis research society international (OARSI) scale on histological sections of injured and uninjured knees. RESULTS Following injury we observed a rapid loss of trabecular bone in injured knees compared to uninjured knees by 7 days post-injury, followed by a partial recovery of trabecular bone to a new steady state by 28 days post-injury. We also observed considerable non-native bone formation by 56 days post-injury. Grading of histological sections revealed deterioration of articular cartilage by 56 days post-injury, consistent with development of mild OA. CONCLUSIONS This study establishes a novel mouse model of PTOA, and describes the time course of musculoskeletal changes following knee injury, helping to establish the window of opportunity for preventative treatment.

The Effect of Anterior Cruciate Ligament Reconstruction on Stride-to-Stride Variability

PURPOSE The purpose of our study was to investigate the functional outcome after anterior cruciate ligament (ACL) reconstruction using bone-patellar tendon-bone (BPTB) and quadrupled semitendinosus and gracilis tendon (ST/G) autografts by evaluating stride-to-stride variability. METHODS Six patients with BPTB and 6 patients with STG ACL reconstruction, 2 years postoperatively, and 6 healthy control subjects walked on a treadmill at a self-selected pace while 2 minutes of continuous kinematic data were recorded with a 6-camera optoelectronic system. Stride-to-stride variability was calculated from the knee flexion/extension data using the nonlinear measure of approximate entropy, which estimates the regularity of movement patterns over time. RESULTS ACL reconstruction affects stride-to-stride variability. Both the BPTB and the ST/G groups had significantly larger approximate entropy values than the healthy controls. No differences were found between the BPTB and the ST/G approximate entropy values. CONCLUSIONS After ACL reconstruction using either BPTB or quadrupled ST/G, there is increased gait variability as compared to healthy individuals. This could be caused by the altered neuromuscular activity found in ACL-reconstructed limbs. LEVEL OF EVIDENCE Level III, case control study.

The effect of growth factors on both collagen synthesis and tensile strength of engineered human ligaments.

Growth factors play a central role in the development and remodelling of musculoskeletal tissues. To determine which growth factors optimized in vitro ligament formation and mechanics, a Box-Behnken designed array of varying concentrations of growth factors and ascorbic acid were applied to engineered ligaments and the collagen content and mechanics of the grafts were determined. Increasing the amount of transforming growth factor (TGF) β1 and insulin-like growth factor (IGF)-1 led to an additive effect on ligament collagen and maximal tensile load (MTL). In contrast, epidermal growth factor (EGF) had a negative effect on both collagen content and MTL. The predicted optimal growth media (50 μg/ml TGFβ, IGF-1, and GDF-7 and 200 μM ascorbic acid) was then validated in two separate trials: showing a 5.7-fold greater MTL and 5.2-fold more collagen than a minimal media. Notably, the effect of the maximized growth media was scalable such that larger constructs developed the same material properties, but larger MTL. These results show that optimizing the interactions between growth factors and engineered ligament volume results in an engineered ligament of clinically relevant function.

Stimulation of the Superficial Zone Protein and Lubrication in the Articular Cartilage by Human Platelet-Rich Plasma

Background: Platelet-rich plasma (PRP) contains high concentrations of autologous growth factors that originate from platelets. Intra-articular injections of PRP have the potential to ameliorate the symptoms of osteoarthritis in the knee. Superficial zone protein (SZP) is a boundary lubricant in articular cartilage and plays an important role in reducing friction and wear and therefore is critical in cartilage homeostasis. Purpose: To determine if PRP influences the production of SZP from human joint-derived cells and to evaluate the lubricating properties of PRP on normal bovine articular cartilage. Study Design: Controlled laboratory study. Methods: Cells were isolated from articular cartilage, synovium, and the anterior cruciate ligament (ACL) from 12 patients undergoing ACL reconstruction. The concentrations of SZP in PRP and culture media were measured by enzyme-linked immunosorbent assay. Cellular proliferation was quantified by determination of cell numbers. The lubrication properties of PRP from healthy volunteers on bovine articular cartilage were investigated using a pin-on-disk tribometer. Results: In general, PRP stimulated proliferation in cells derived from articular cartilage, synovium, and ACL. It also significantly enhanced SZP secretion from synovium- and cartilage-derived cells. An unexpected finding was the presence of SZP in PRP (2.89 ± 1.23 μg/mL before activation and 3.02 ± 1.32 μg/mL after activation). In addition, under boundary mode conditions consisting of high loads and low sliding speeds, nonactivated and thrombin-activated PRP decreased the friction coefficient (μ = 0.012 and μ = 0.015, respectively) compared with saline (μ = 0.047, P < .004) and high molecular weight hyaluronan (μ = 0.080, P < .006). The friction coefficient of the cartilage with PRP was on par with that of synovial fluid. Conclusion: PRP significantly stimulates cell proliferation and SZP secretion by articular cartilage and synovium of the human knee joint. Furthermore, PRP contains endogenous SZP and, in a functional bioassay, lubricates bovine articular cartilage explants. Clinical Relevance: These findings provide evidence to explain the biochemical and biomechanical mechanisms underlying the efficacy of PRP treatment for osteoarthritis or damage in the knee joint.

Estrogen inhibits lysyl oxidase and decreases mechanical function in engineered ligaments

Women are more likely to suffer an anterior cruciate ligament (ACL) rupture than men, and the incidence of ACL rupture in women rises with increasing estrogen levels. We used an engineered ligament model to determine how an acute rise in estrogen decreases the mechanical properties of ligaments. Using fibroblasts isolated from human ACLs from male or female donors, we engineered ligaments and determined that ligaments made from female ACL cells had more collagen and were equal in strength to those made from male ACL cells. We then treated engineered ligaments for 14 days with low (5 pg/ml), medium (50 pg/ml), or high (500 pg/ml) estrogen, corresponding to the range of in vivo serum estrogen concentrations and found that collagen within the grafts increased without a commensurate increase in mechanical strength. Mimicking the menstrual cycle, with 12 days of low estrogen followed by 2 days of physiologically high estrogen, resulted in a decrease in engineered ligament mechanical function with no change in the amount of collagen in the graft. The decrease in mechanical stiffness corresponded with a 61.7 and 76.9% decrease in the activity of collagen cross-linker lysyl oxidase with 24 and 48 h of high estrogen, respectively. Similarly, grafts treated with the lysyl oxidase inhibitor β-aminoproprionitrile (BAPN) for 24 h showed a significant decrease in ligament mechanical strength [control (CON) = 1.58 ± 0.06 N; BAPN = 1.06 ± 0.13 N] and stiffness (CON = 7.7 ± 0.46 MPa; BAPN = 6.1 ± 0.71 MPa) without changing overall collagen levels (CON = 396 ± 11.5 μg; BAPN = 382 ± 11.6 μg). Together, these data suggest that the rise in estrogen during the follicular phase decreases lysyl oxidase activity in our engineered ligament model and if this occurs in vivo may decrease the stiffness of ligaments and contribute to the elevated rate of ACL rupture in women.

The exercise-induced biochemical milieu enhances collagen content and tensile strength of engineered ligaments.

Exercise acutely increases the concentrations of metabolites and hormones such as growth hormone (GH) and, to a lesser extent, insulin‐like growth factor 1 (IGF‐1); however, the biological function of this response is unclear. Pharmacological administration of these hormones stimulates collagen synthesis in muscle and tendon; however, whether the post‐exercise biochemical milieu has a similar action is unknown. Treating engineered ligaments with serum obtained from young healthy men after exercise resulted in more collagen and improved tensile strength over those treated with serum from resting men. Further, we show that the increase in collagen induced by post‐exercise serum (i) is not reproduced by treatment with recombinant GH or IGF‐1, and (ii) is associated with the activation of PI3 kinase/mTORC1 and ERK1/2 signalling.

Neuromuscular recovery after distraction osteogenesis at different frequencies in a rabbit model.

Abstract: The muscle and nerve responses to stresses applied during distraction osteogenesis have not been clearly defined. This study hypothesized that distraction resulting in 30% lengthening decreases muscle force generation of the lengthened muscle and increasing the frequency of distraction attenuates the decrease of force generation accompanying lengthening. This study investigated the effects of different distraction frequencies on neuromuscular recovery in a rabbit model. Animals were assigned into group 1 (low-frequency distraction) and group 2 (high-frequency distraction). Distraction was continued until a 30% increase in the original tibial length was achieved. After consolidation of the osteotomy, knee and ankle range of motion, muscle force generation, and neuromuscular junction parameters were evaluated. Lengthening of 30% resulted in significantly decreased range of motion compared with the control leg (P < 0.05). Lengthening of 30% also substantially decreased force generation of the peroneus longus muscle. However, force generation of the peroneus longus muscle in the high-frequency group was 70.5% ± 6.5% of the control side, significantly higher than that in the low-frequency distraction group (49.7% ± 4.8% of the control side, P < 0.05). There was no statistical difference between the 2 groups in neuromuscular junction morphology, although an abnormal shape of the postsynaptic neuromuscular junction was observed after distraction. The use of a high-frequency distraction technique during limb lengthening may result in a reduction in impairment of knee and ankle range of motion and improved muscle function compared with that observed with the use of low-frequency distraction. Repeated microtrauma to the soft tissues associated with high-frequency distraction may facilitate the regenerative capacity of the soft tissues and result in an improved outcome of muscle and nerve function.

Editorial Commentary: PRP: Platelet-Rich Plasma or Promising but Rarely Proven?

Cost-utility analysis using a Markov decision model finds that platelet-rich plasma (PRP) is not cost-effective in rotator cuff repair because of no added outcomes benefit or improvement in retear rate according to best current evidence (Level I to III studies). To achieve the willingness-to-pay threshold, PRP would need to reduce rotator cuff retear rates. The authors have opened dialogue for us to determine what is the value and what should be the cost for PRP when it comes to rotator cuff repair.

Localized BMP-4 release improves the enthesis of engineered bone-to-bone ligaments

Successful anterior cruciate ligament (ACL) reconstruction requires a functional enthesis, the interface between a bone and ligament or tendon. The enthesis normally exhibits a gradient of tissue phenotypes to smooth the transition from the compliant ligament to stiff bone and decrease stress concentrations between the 2 tissues. However, this structure does not fully regenerate after surgical repair leading to increased rupture rates and incidence of osteoarthritis. We have previously engineered ligaments between 2 cylindrical brushite cement anchors using human ACL fibroblasts entrapped in a fibrin gel. Using this model, we hypothesized that the local application and release of growth factors from the brushite cement anchors will promote fibrocartilage formation and improve interface failure load. Of 5 chondrogenic growth factors (BMP‐2, BMP‐4, and BMP‐7 and TGF‐β1 and TGF‐β3) tested, we identified TGF‐β1 as having a significant negative effect (P = .0001), while the local release of BMP‐4 at the enthesis of engineered ligaments improved the interface failure load by up to 38% compared to control conditions. BMP‐4 treatment increased the expression of the enthesis‐related genes Sox9, aggrecan, and tenascin C and the inhibitor of mineralization osteopontin. These data suggest that BMP‐4 drives a shift toward a fibrocartilaginous phenotype resulting in a stronger engineered enthesis.