Purpose Animal models are an indispensable tool for developing and testing new clinical applications regarding the treatment of acute injuries and chronic diseases of the knee joint. Therefore, the purpose of this study was to compare the anatomy of the intra-articular structures of the human knee to species commonly used in large animal research studies. Methods Fresh frozen cow (n=4), sheep (n=3), goat (n=4), dog (n=4), pig (n=5), rabbit (n=5), and human (n=4) cadaveric knees were used. Passive range of motion and intra-articular structure sizes of the knees were measured, the structure sizes normalized to the tibial plateau, and compared among the species. Results Statistically significant differences in the range of motion and intra-articular structure sizes were found among all the species. Only the human knee was able to attain full extension. After normalization, only the pig ACL was significantly longer than the human counterpart. The tibial insertion site of the ACL was split by the anterior lateral meniscus attachment in the cow, sheep, and pig knees. The sheep PCL had two distinct tibial insertion sites, while all the other knees had only one. Furthermore, only in human knees, both lateral meniscal attachments were located more centrally than the medial meniscal attachments. Conclusions/Clinical Relevance Despite the relatively preserved dimensions of the cruciate ligaments, menisci, and intercondylar notch amongst human and animals, structural differences in the cruciate ligament attachment sites and morphology of the menisci between humans and animals are important to consider when selecting an animal model.

Background: Preclinical studies suggest that for complete midsubstance anterior cruciate ligament (ACL) injuries, a suture repair of the ACL augmented with a protein implant placed in the gap between the torn ends (bridge-enhanced ACL repair [BEAR]) may be a viable alternative to ACL reconstruction (ACLR). Hypothesis: We hypothesized that patients treated with BEAR would have a noninferior patient-reported outcomes (International Knee Documentation Committee [IKDC] Subjective Score; prespecified noninferiority margin, –11.5 points) and instrumented anteroposterior (AP) knee laxity (prespecified noninferiority margin, +2-mm side-to-side difference) and superior muscle strength at 2 years after surgery when compared with patients who underwent ACLR with autograft. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: One hundred patients (median age, 17 years; median preoperative Marx activity score, 16) with complete midsubstance ACL injuries were enrolled and underwent surgery within 45 days of injury. Patients were randomly assigned to receive either BEAR (n = 65) or autograft ACLR (n = 35 [33 with quadrupled semitendinosus-gracilis and 2 with bone–patellar tendon–bone]). Outcomes—including the IKDC Subjective Score, the side-to-side difference in instrumented AP knee laxity, and muscle strength—were assessed at 2 years by an independent examiner blinded to the procedure. Patients were unblinded after their 2-year visit. Results: In total, 96% of the patients returned for 2-year follow-up. Noninferiority criteria were met for both the IKDC Subjective Score (BEAR, 88.9 points; ACLR, 84.8 points; mean difference, 4.1 points [95% CI, –1.5 to 9.7]) and the side-to-side difference in AP knee laxity (BEAR, 1.61 mm; ACLR, 1.77 mm; mean difference, –0.15 mm [95% CI, –1.48 to 1.17]). The BEAR group had a significantly higher mean hamstring muscle strength index than the ACLR group at 2 years (98.2% vs 63.2%; P < .001). In addition, 14% of the BEAR group and 6% of the ACLR group had a reinjury that required a second ipsilateral ACL surgical procedure ( P = .32). Furthermore, the 8 patients who converted from BEAR to ACLR in the study period and returned for the 2-year postoperative visit had similar primary outcomes to patients who had a single ipsilateral ACL procedure. Conclusion: BEAR resulted in noninferior patient-reported outcomes and AP knee laxity and superior hamstring muscle strength when compared with autograft ACLR at 2-year follow-up in a young and active cohort. These promising results suggest that longer-term studies of this technique are justified. Registration: NCT02664545 (ClinicalTrials.gov identifier)

Background:This study assessed the safety of the newly developed bridge-enhanced anterior cruciate ligament (ACL) repair (BEAR), which involves suture repair of the ligament combined with a bioactive scaffold to bridge the gap between the torn ligament ends. As the intra-articular environment is complex in its response to implanted materials, this study was designed to determine whether there would be a significant rate of adverse reaction to the implanted scaffold.Hypothesis:The primary hypothesis was that the implanted scaffold would not result in a deep joint infection (arthrocentesis with positive culture) or significant inflammation (clinical symptoms justifying arthrocentesis but negative culture). The secondary hypotheses were that patients treated with BEAR would have early postoperative outcomes that were similar to patients treated with ACL reconstruction with an autologous hamstring graft.Study Design:Cohort study; Level of evidence, 2.Methods:A total of 20 patients were enrolled in this nonrandomized, first-in-human study. Ten patients received BEAR treatment and 10 received a hamstring autograft ACL reconstruction. The BEAR procedure was performed by augmenting a suture repair with a proprietary scaffold, the BEAR scaffold, placed in between the torn ends of the ACL at the time of suture repair. The BEAR scaffold is to our knowledge the only device that fills the gap between the torn ligament ends to have current Investigational Device Exemption approval from the Food and Drug Administration. Ten milliliters of autologous whole blood were added to the scaffold prior to wound closure. Outcomes were assessed at 3 months postoperatively. The outcomes measures included postoperative pain, muscle atrophy, loss of joint range of motion, and implant failure (designated by an International Knee Documentation Committee grade C or D Lachman test and/or an absence of continuous ACL tissue on magnetic resonance images).Results:There were no joint infections or signs of significant inflammation in either group. There were no differences between groups in effusion or pain, and no failures by Lachman examination criteria (BEAR, 8 grade A and 2 grade B; ACL reconstruction, 10 grade A). Magnetic resonance images from all of the BEAR and ACL-reconstructed patients demonstrated a continuous ACL or intact graft. In addition, hamstring strength at 3 months was significantly better in the BEAR group than in the hamstring autograft group (mean ± SD: 77.9% ± 14.6% vs 55.9% ± 7.8% of the contralateral side; P < .001).Conclusion:The results of this study suggest that the BEAR procedure may have a rate of adverse reactions low enough to warrant a study of efficacy in a larger group of patients.

Background:Bridge-enhanced anterior cruciate ligament repair (BEAR) combines suture repair of the anterior cruciate ligament (ACL) with a specific extracellular matrix scaffold (the BEAR scaffold) that is placed in the gap between the torn ends of the ACL to facilitate ligament healing.Purpose/Hypothesis:The purpose of this study was to report the 12- and 24-month outcomes of patients who underwent the BEAR procedure compared with a nonrandomized concurrent control group who underwent ACL reconstruction (ACLR) with an autograft. We hypothesized that the BEAR group would have physical examination findings, patient-reported outcomes, and adverse events that were similar to those of the ACLR group.Study Design:Cohort study; Level of evidence, 2.Methods:Ten patients underwent BEAR, and 10 underwent ACLR with a 4-stranded hamstring autograft. At 24 months, 9 of the 10 BEAR patients and 7 of the 10 ACLR patients completed a study visit. Outcomes reported included International Knee Documentation Committee (IKDC) subjective and objective results, knee anteroposterior (AP) laxity findings via an arthrometer, and functional outcomes.Results:There were no graft or repair failures in the first 24 months after surgery. The IKDC subjective scores in both groups improved significantly from baseline (P < .0001) at 12 and 24 months, to 84.6 ± 17.2 in the ACLR group and to 91.7 ± 11.7 in the BEAR group. An IKDC objective grade of A (normal) was found in 44% of patients in the BEAR group and in 29% of patients in the ACLR group at 24 months; no patients in either group had C (abnormal) or D (severely abnormal) grades. Arthrometer testing demonstrated mean side-to-side differences in AP laxity that were similar in the 2 groups at 24 months (BEAR, 1.94 ± 2.08 mm; ACLR, 3.14 ± 2.66 mm). Functional hop testing results were similar in the 2 groups at 12 and 24 months after surgery. Hamstring strength indices were significantly higher in the BEAR group compared with the ACLR group (P = .0001).Conclusion:In this small, first-in-human study, BEAR produced similar outcomes to ACLR with a hamstring autograft. BEAR may result in knee stability and patient-reported outcomes at 2 years sufficient to warrant longer term studies of efficacy in larger groups of patients.

IntroductionThe present study compares bone morphogenetic protein (BMP)-4 and BMP-2 gene transfer as agents of chondrogenesis and hypertrophy in human primary mesenchymal stem cells (MSCs) maintained as pellet cultures.MethodsAdenoviral vectors carrying cDNA encoding human BMP-4 (Ad.BMP-4) were constructed by cre-lox combination and compared to previously generated adenoviral vectors for BMP-2 (Ad.BMP-2), green fluorescent protein (Ad.GFP), or firefly luciferase (Ad.Luc). Cultures of human bone-marrow derived MSCs were infected with 5 × 102 viral particles/cell of Ad.BMP-2, or Ad.BMP-4, seeded into aggregates and cultured for three weeks in a defined, serum-free medium. Untransduced cells or cultures transduced with marker genes served as controls. Expression of BMP-2 and BMP-4 was determined by ELISA, and aggregates were analyzed histologically, immunohistochemically, biochemically and by RT-PCR for chondrogenesis and hypertrophy.ResultsLevels of BMP-2 and BMP-4 in the media were initially 30 to 60 ng/mL and declined thereafter. BMP-4 and BMP-2 genes were equipotent inducers of chondrogenesis in primary MSCs as judged by lacuna formation, strong staining for proteoglycans and collagen type II, increased levels of GAG synthesis, and expression of mRNAs associated with the chondrocyte phenotype. However, BMP-4 modified aggregates showed a lower tendency to progress towards hypertrophy, as judged by expression of alkaline phosphatase, annexin 5, immunohistochemical staining for type X collagen protein, and lacunar size.ConclusionsBMP-2 and BMP-4 were equally effective in provoking chondrogenesis by primary human MSCs in pellet culture. However, chondrogenesis triggered by BMP-2 and BMP-4 gene transfer showed considerable evidence of hypertrophic differentiation, with, the cells resembling growth plate chondrocytes both morphologically and functionally. This suggests caution when using these candidate genes in cartilage repair.

Objective Post-traumatic osteoarthritis (PTOA) occurs after anterior cruciate ligament (ACL) injury. PTOA may be initiated by early expression of proteolytic enzymes capable of causing degradation of the articular cartilage at time of injury. This study investigated the production of three of these key proteases in multiple joint tissues after ACL injury and subsequent markers of cartilage turnover. Design ACL transection was performed in adolescent minipigs. Collagenase (MMP-1 and MMP-13) and aggrecanase (ADAMTS-4) gene expression changes were quantified in the articular cartilage, synovium, injured ligament, and the provisional scaffold at days 1, 5, 9, and 14 post-injury. Markers of collagen degradation (C2C), synthesis (CPII) and aggrecan synthesis (CS846) were quantified in the serum and synovial fluid. Histologic assessment of the cartilage integrity (OARSI scoring) was also performed. Results MMP-1 gene expression was upregulated in the articular cartilage, synovium and ligament after ACL injury. MMP-13 expression was suppressed in the articular cartilage, but upregulated 100fold in the synovium and ligament. ADAMTS-4 was upregulated in the synovium and ligament but not in the articular cartilage. The concentration of collagen degradation fragments (C2C) in the synovial joint fluid nearly doubled in the first five days after injury. Conclusion We conclude that upregulation of genes coding for proteins capable of degrading cartilage ECM is seen within the first few days after ACL injury, and this response is seen not only in chondrocytes, but also in cells in the synovium, ligament and provisional scaffold.

our time-specific, T *-based regression model may allow us to estimate the structural properties of ACL repairs in vivo longitudinally. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1701-1709, 2018.

Synovial fluid in an articulating joint contains proteins derived from the blood plasma and proteins that are produced by cells within the joint tissues, such as synovium, cartilage, ligament, and meniscus. The proteome composition of healthy synovial fluid and the cellular origins of many synovial fluid components are not fully understood. Here, we present a normative proteomics study using porcine synovial fluid. Using our optimized method, we identified 267 proteins with high confidence in healthy synovial fluid. We also evaluated mRNA expression data from tissues that can contribute to the synovial fluid proteome, including synovium, cartilage, blood, and liver, to better estimate the relative contributions from these sources to specific synovial fluid components. We identified 113 proteins in healthy synovial fluid that appear to be primarily derived from plasma transudates, 37 proteins primarily derived from synovium, and 11 proteins primarily derived from cartilage. Finally, we compared the identified synovial fluid proteome to the proteome of human plasma, and we found that the two body fluids share many similarities, underlining the detected plasma derived nature of many synovial fluid components. Knowing the synovial fluid proteome of a healthy joint will help to identify mechanisms that cause joint disease and pathways involved in disease progression.