Surgical restabilization reduces the progression of post-traumatic osteoarthritis initiated by ACL rupture in mice.

OBJECTIVE: People who sustain joint injuries such as anterior cruciate ligament (ACL) rupture often develop post-traumatic osteoarthritis (PTOA). In human patients, ACL injuries are often treated with ACL reconstruction. However, it is still unclear how effective joint restabilization is for reducing the progression of PTOA. The goal of this study was to determine how surgical restabilization of a mouse knee joint following non-invasive ACL injury affects PTOA progression. DESIGN: In this study, 187 mice were subjected to non-invasive ACL injury or no injury. After injury, mice underwent restabilization surgery, sham surgery, or no surgery. Mice were then euthanized on day 14 or day 49 after injury/surgery. Functional analyses were performed at multiple time points to assess voluntary movement, gait, and pain. Knees were analyzed ex vivo with micro-computed tomography, RT-PCR, and whole-joint histology to assess articular cartilage degeneration, synovitis, and osteophyte formation. RESULTS: Both ACL injury and surgery resulted in loss of epiphyseal trabecular bone (-27-32%) and reduced voluntary movement at early time points. Joint restabilization successfully lowered OA score (-78% relative to injured at day 14, p < 0.0001), and synovitis scores (-37% relative to injured at day 14, p = 0.042), and diminished the formation of chondrophytes/osteophytes (-97% relative to injured at day 14, p < 0.001, -78% at day 49, p < 0.001). CONCLUSIONS: This study confirmed that surgical knee restabilization was effective at reducing articular cartilage degeneration and diminishing chondrophyte/osteophyte formation after ACL injury in mice, suggesting that these processes are largely driven by joint instability in this mouse model. However, restabilization was not able to mitigate the early inflammatory response and the loss of epiphyseal trabecular bone, indicating that these processes are independent of joint instability.

Trends in Orthopaedic Surgery Workforce Diversity: Analyzing Changes Over Time.

INTRODUCTION: There are many reasons why orthopaedic surgeons move or change careers. We asked the questions: (1) What is the geographic distribution of orthopaedic surgeons with respect to age, sex, and race and ethnicity? (2) How has our workforce changed over time with regard to these factors? (3) Are there any patterns or trends detected regarding policy or regulatory events that coincide with these differences? METHODS: The American Academy of Orthopaedic Surgeons surveys over 30,000 members, collecting data on demographics, age, race sex, and practice statistics. We calculated geographic distributions and evaluated these differences over time-potential influences from malpractice suits or tort reform were investigated. RESULTS: Overall surgeon density increased over time. The largest negative changes were noted in District of Columbia, Wyoming, and North Dakota and positive changes in Colorado, South Dakota, and West Virginia. Age across all states increased (mean 1.7 years). Number of female surgeons increased in most states (4.6% to 5.7%). Number of African Americans increased from 1.6% to 1.8%, Hispanic/LatinX from 1.8% to 2.2%, Asian from 5.5% to 6.7%, and multiracial from 0.8% to 1.2%. No change was noted in the percentage of Native American surgeons. DISCUSSION: Surgeon density increased from 2012 to 2018; the cause for this change was not evident. Small increases in surgeon population, female surgeons, and in some underrepresented minorities were seen.

Improving Technical Outcome in Osteochondral Allograft Transplantation of the Femoral Trochlea: The Role of Contoured Guides, Experience Level, Graft Size, and Graft Position.

Background: The use of coring instrumentation for osteochondral allograft (OCA) transplantation of the femoral trochlea is challenging due to the complex topography of this anatomical area. Purpose: We sought to determine the effect of flat guides versus guides contoured to the surface of the trochlea on graft step-off in trochlear OCAs performed on a foam bone model. We also determined the effect of surgeon experience level and graft size on step-off. Study Design: Controlled laboratory study. Methods: Allograft harvesters were produced in 3 different sequential sizes with either a flat or a contoured undersurface. The guides matched one another in all aspects of shape and size except for the undersurface contour. The contoured undersurface generally matched the surface of the bone model trochlea but was not customized to that surface. A total of 72 foam femora were obtained. Identical trochlear stellate lesions of 3 different sizes (small, medium, and large) were created using 3-dimensional printed surface templates. A total of 6 surgeons (3 attending and 3 resident surgeons) performed OCAs of each trochlear lesion. Each surgeon performed 1 graft for each size and each guide type (n = 6 per surgeon). A specialized digital caliper was prepared that allowed the measurement of graft step-off to within 0.01 mm at a distance of 5 mm between the 2 sensors. The measurements were performed at 8 positions around the clockface of the grafts. Results: Grafts performed with the contoured guides had a mean step-off of 0.43 ± 0.37 mm. Grafts performed with the flat guides had a mean step-off of 0.74 ± 0.78 mm (P < .0001). Experience level did not have a significant effect on graft step-off (P = .81). There was no identifiable pattern indicating higher step-off at any one position on the clockface. Conclusion: In this study, contoured grafts had significantly lower step-offs compared with flat guides. Experience level, clockface position, and graft size did not affect step-off.

Chondrocalcinosis and Osteoarthritis: A Literature Review.

OBJECTIVE: The objective of this study was to review the literature on associations between chondrocalcinosis (CC) and osteoarthritis (OA) and to examine the role of colchicine, previously established as effective for calcium pyrophosphate deposition disease, in the treatment of OA. METHODS: A literature search for mechanistic and clinical studies published between 1990 and 2021 listed in PubMed was performed and studies were included if they examined the associations between OA and CC or colchicine using relevant search terms. RESULTS: Published evidence suggests significant radiographic and mechanistic associations between knee OA and knee CC, but there are only a limited number of studies demonstrating associations between OA and CC in the hips, hands, and ankles. We examined three studies testing the efficacy of colchicine on treatment of pain in OA and found insufficient evidence to definitively establish that colchicine is effective to ameliorate symptoms of OA, although differences in study methodologies and inclusion criteria may explain inconsistent study findings. CONCLUSION: An association between CC and OA is supported at the knee joint in both radiographic and in-vitro studies, but is less definite when the relationship is evaluated at other joints, including at the hips, hands, and ankles. Further research is required to ascertain whether CC modifies symptoms in patients with osteoarthritis or is associated with OA progression. It may be worthwhile to further evaluate colchicine or other agents for potential symptom modifying roles in OA or in OA with CC.

A Fresh Glimpse into Cartilage Immune Privilege.

The increasing prevalence of degenerative cartilage disorders in young patients is a growing public concern worldwide. Cartilage's poor innate regenerative capacity has inspired the exploration and development of cartilage replacement treatments such as tissue-engineered cartilages and osteochondral implants as potential solutions to cartilage loss. The clinical application of tissue-engineered implants is hindered by the lack of long-term follow-up demonstrating efficacy, biocompatibility, and bio-integration. The historically reported immunological privilege of cartilage tissue was based on histomorphological observations pointing out the lack of vascularity and the presence of a tight extracellular matrix. However, clinical studies in humans and animals do not unequivocally support the immune-privilege theory. More in-depth studies on cartilage immunology are needed to make clinical advances such as tissue engineering more applicable. This review analyzes the literature that supports and opposes the concept that cartilage is an immune-privileged tissue and provides insight into mechanisms conferring various degrees of immune privilege to other, more in-depth studied tissues such as testis, eyes, brain, and cancer.

The immediate meniscal allograft transplantation achieved better chondroprotection and less meniscus degeneration than the conventional delayed transplantation in the long-term.

PURPOSE: The purpose of this study was to compare the long-term clinical and radiological outcomes between the immediate and delayed meniscus allograft transplantation (MAT). METHODS: Nine menisci were transplanted immediately after total meniscectomy (immediate group, IM), and 10 menisci were delayed transplanted in patients with the median of 35 months (range 9-92 months) after total meniscectomy (delayed group, DE). Patient's subjective clinical outcomes including VAS, IKDC, Lysholm and Tegner scores as well as muscle strength measures were compared. Joint degeneration was evaluated by both radiographs to assess joint space width narrowing, Kellegren-Lawrence (KL) grade and MRI with T2 mapping sequences to quantitatively analyze both cartilage and meniscal allograft degeneration. RESULTS: The median follow-up time was 10.8 years (range 10-14 years). The IKDC (IM vs DE, 89.8 vs 80.9, n.s.) and Lysholm scores (IM vs DE, 87.7 vs 78.0, n.s.) were close in two groups, while the IM group showed slightly lower VAS (IM vs DE, 0.2 vs 1.5, p = 0.031), higher Tegner score (IM vs DE, 7 vs 3.5 p = 0.021) and better quadriceps muscle strength. The IM group had less joint space narrowing (IM vs DE, 0.35 mm vs 0.71 mm, n.s.), less KL grade progression (IM vs DE, 0.6 vs 1.7, p = 0.041) on radiographs and less chondral lesions development on MRIs (Cartilage Degeneration Index, IM vs DE, 252 vs 2038, p = 0.025). All meniscal grafts exhibited degeneration by showing grade 3 signal on MRI, and 4 (4/9) in the IM group and 8 (8/10) cases in the DE group. The T2 value of cartilage and meniscal allograft in the IM group was close to that of the healthy control and was significantly lower than that of the DE group. CONCLUSION: Compared to the conventional delayed MAT, the immediate MAT achieved better cartilage and meniscus protection in the long-term, while its superiority in patient-reported outcomes was limited. LEVEL OF EVIDENCE: IV.

Next Steps: Advocating for Women in Orthopaedic Surgery.

Orthopaedic surgery is the least diverse of all medical specialties, by both sex and race. Diversity among orthopaedic trainees is the lowest in medicine, and growth in percentage representation is the lowest of all surgical subspecialties. Women comprise only 6% of orthopaedic surgeons and 16% of orthopaedic surgery trainees. This extreme lack of diversity in orthopaedics limits creative problem-solving and the potential of our profession. Women in orthopaedics encounter sexual harassment, overt discrimination, and implicit bias, which create barriers to training, career satisfaction, and success. Women are underrepresented in leadership positions, perpetuating the lack of diversity through poor visibility to potential candidates, which impedes recruitment. Correction will require a concerted effort, as acknowledged by the American Academy of Orthopaedic Surgeons leadership who included a goal and plan to increase diversity in the 2019 to 2023 Strategic Plan. Recommended initiatives include support for pipeline programs that increase diversity of the candidate pool; sexual harassment and implicit bias acknowledgement, education, and corrective action; and the active sponsorship of qualified, capable women by organizational leaders. To follow, women will lend insight from their diverse viewpoints to research questions, practice problems, and clinical conundrums of our specialty, augmenting the profession and improving patient outcomes.

Prognostic Factors to Determine Survivorship of Meniscal Allograft Transplant: A Systematic Review.

BACKGROUND: There is much room for improvement and optimization of meniscal allograft survivorship. PURPOSE: To understand prognostic factors for survivorship using evidence-based selection criteria in order to identify patients who would best benefit from meniscal allograft transplant (MAT). STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: We conducted this systematic review to analyze prognostic factors for survivorship of MAT. The Cochrane Central Register, PubMed publisher, Embase.com, and Web of Science databases were searched through August 8, 2019. Included studies entailed patients of any age who received MAT with a reported association between prognostic factors and survivorship of the allograft. Two reviewers independently screened all titles and abstracts for eligibility, extracted the data, assessed the risk of bias using the Newcastle-Ottawa Scale, and performed a best-evidence synthesis. RESULTS: The review included 18 studies with a total of 1920 patients. The mean follow-up time was 6.0 years (range, 2.1-11.2 years). A total of 20 prognostic factors were identified and shown to be associated with survivorship of MAT. Strong evidence was found that severe cartilage damage was associated with poor survivorship. Strong evidence was also found showing that sex, knee compartment, surgical side, concomitant anterior cruciate ligament (ACL) reconstruction, and concomitant osteotomy for malalignment had no effect on survivorship. Moderate evidence was found that body mass index (<36), tobacco use, and arthroscopic versus open procedure had no influence on survivorship. Conflicting evidence was found that older age and kissing cartilage lesions (lesions on both the femur and tibia vs on a single side) decreased survivorship. CONCLUSION: Severe cartilage damage decreases the survivorship of MAT. Concomitant ACL reconstruction and osteotomy showed no relationship to survivorship. Many determinants showed conflicting and limited evidence. Older age may be of interest and should be further studied.

Consensus on Rehabilitation Guidelines among Orthopedic Surgeons in the United States following Use of Third-Generation Articular Cartilage Repair (MACI) for Treatment of Knee Cartilage Lesions.

OBJECTIVE: The aim of this study was to evaluate levels of consensus in rehabilitation practices following MACI (autologous cultured chondrocytes on porcine collagen membrane) treatment based on the experience of an expert panel of U.S. orthopedic surgeons. DESIGN: A list of 24 questions was devised based on the current MACI rehabilitation protocol, literature review, and discussion with orthopedic surgeons. Known areas of variability were used to establish 4 consensus domains, stratified on lesion location (tibiofemoral [TF] or patellofemoral [PF]), including weightbearing (WB), range of motion (ROM), return to work/daily activities of living, and return to sports. A 3-step Delphi technique was used to establish consensus. RESULTS: Consensus (>75% agreement) was achieved on all 4 consensus domains. Time to full WB was agreed as immediate (with bracing) for PF patients (dependent on concomitant procedures), and 7 to 9 weeks in TF patients. A progression for ROM was agreed that allowed patients to reach 90° by week 4, with subsequent progression as tolerated. The panel estimated that the time to full ROM would be 7 to 9 weeks on average. A range of time was established for release to activities of daily living, work, and sports, dependent on lesion and patient characteristics. CONCLUSIONS: Good consensus was established among a panel of U.S. surgeons for rehabilitation practices following MACI treatment of knee cartilage lesions. The consensus of experts can aid surgeons and patients in the expectations and rehabilitation process as MACI surgery becomes more prevalent in the United States.

Effects of Micronized Cartilage Matrix on Cartilage Repair in Osteochondral Lesions of the Talus.

BACKGROUND: The repair of osteochondral lesions remains a challenge due to its poor vascularity and limited healing potential. Micronized cartilage matrix (MCM) is dehydrated, decellularized, micronized allogeneic cartilage matrix that contains the components of native articular tissue and is hypothesized to serve as a scaffold for the formation of hyaline-like tissue. Our objective was to demonstrate in vitro that the use of MCM combined with mesenchymal stem cells (MSCs) can lead to the formation of hyaline-like cartilage tissue in a single-stage treatment model. DESIGN: In group 1 (no wash), 250 µL MCM was reconstituted in 150 µL Dulbecco's phosphate-buffered saline (DPBS) for 5 minutes. Group 2 (saline wash) included 250 µL MCM washed in 20 mL DPBS for 30 minutes, then aspirated to remove all DPBS and reconstituted in 150 µL DPBS. Group 3 (serum wash): 250µL MCM washed in 20 mL DPBS for 30 minutes, then aspirated and reconstituted in 150 µL fetal bovine serum. Each group was then added to 50 µL solution of MSC suspended in DPBS at a concentration of 1.2 × 106 cells/350 µL. After 3 weeks, the defects were extracted and sectioned to perform viability and histologic analyses. RESULTS: Stem cells without rehydration of the MCM showed almost no viability whereas near complete cell viability was seen after rehydration with serum or saline solution, ultimately leading to chondrogenic differentiation and adhesion to the MCM particles. CONCLUSION: We have shown in this proof-of-concept in vitro study that MCM can serve as a scaffold for the growth of cartilage tissue for the treatment of osteochondral lesions.

Surgical and tissue engineering strategies for articular cartilage and meniscus repair.

Injuries to articular cartilage and menisci can lead to cartilage degeneration that ultimately results in arthritis. Different forms of arthritis affect ~50 million people in the USA alone, and it is therefore crucial to identify methods that will halt or slow the progression to arthritis, starting with the initiating events of cartilage and meniscus defects. The surgical approaches in current use have a limited capacity for tissue regeneration and yield only short-term relief of symptoms. Tissue engineering approaches are emerging as alternatives to current surgical methods for cartilage and meniscus repair. Several cell-based and tissue-engineered products are currently in clinical trials for cartilage lesions and meniscal tears, opening new avenues for cartilage and meniscus regeneration. This Review provides a summary of surgical techniques, including tissue-engineered products, that are currently in clinical use, as well as a discussion of state-of-the-art tissue engineering strategies and technologies that are being developed for use in articular cartilage and meniscus repair and regeneration. The obstacles to clinical translation of these strategies are also included to inform the development of innovative tissue engineering approaches.

The medial epicondyle of the distal femur is the optimal location for MRI measurement of semitendinosus and gracilis tendon cross-sectional area.

PURPOSE: Graft diameter ≥ 8 mm reduces the risk of failure after anterior cruciate ligament reconstruction (ALCR) with hamstring tendon autograft. Pre-operative measurement of gracilis (GT) and semitendinosus (ST) cross-sectional area using MRI has been utilized but the optimal location for measurement is unknown. The main purpose of this study was to examine the cross-sectional areas of GT + ST at different locations and develop a model to predict whether a doubled hamstring graft of GT + ST will be of sufficient cross-sectional area for ACLR. METHODS: A retrospective review was performed of 154 patients who underwent primary ACLR using doubled hamstring autograft. Cross-sectional area measurements of GT + ST on pre-operative MRI axial images were made at three locations: medial epicondyle (ME), tibiofemoral joint line (TJL), and tibial physeal scar (TPS) and calculated the correlation of intra-operative graft size for each location using the Pearson's correlation coefficient. A receiver operating characteristic (ROC) established a threshold that would predict graft diameter ≥ 8 mm. RESULTS: Measurement of GT + ST at the ME had a stronger correlation (r = 0.389) to intra-operative graft diameter than measurements at the TJL (r = 0.256) or TPS (r = 0.240). The ROC indicated good predictive value for hamstring graft diameter ≥ 8 mm based on MRI measurement at the ME with the optimal threshold with the highest sensitivity and specificity as 18 mm2. CONCLUSION: Cross-sectional area measurement of GT + ST at the ME correlated most closely to intra-operative diameter of a doubled hamstring autograft compared to measurements at the TJL or the TPS. As graft diameter < 8 mm is correlated with higher failure rates of ACL surgery, the ability to pre-operatively predict graft diameter is clinically useful. LEVEL OF EVIDENCE: Level III, prognostic study.

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.

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

Exercise stimulates a dramatic change in the concentration of circulating hormones, such as growth hormone (GH), but the biological functions of this response are unclear. Pharmacological GH administration stimulates collagen synthesis; however, whether the post-exercise systemic milieu has a similar action is unknown. We aimed to determine whether the collagen content and tensile strength of tissue-engineered ligaments is enhanced by serum obtained post-exercise. Primary cells from a human anterior cruciate ligament (ACL) were used to engineer ligament constructs in vitro. Blood obtained from 12 healthy young men 15 min after resistance exercise contained GH concentrations that were ∼7-fold greater than resting serum (P < 0.001), whereas IGF-1 was not elevated at this time point (P = 0.21 vs. rest). Ligament constructs were treated for 7 days with medium supplemented with serum obtained at rest (RestTx) or 15 min post-exercise (ExTx), before tensile testing and collagen content analysis. Compared with RestTx, ExTx enhanced collagen content (+19%; 181 ± 33 vs. 215 ± 40 µg per construct P = 0.001) and ligament mechanical properties - maximal tensile load (+17%, P = 0.03 vs. RestTx) and ultimate tensile strength (+10%, P = 0.15 vs. RestTx). In a separate set of engineered ligaments, recombinant IGF-1, but not GH, enhanced collagen content and mechanics. Bioassays in 2D culture revealed that acute treatment with post-exercise serum activated mTORC1 and ERK1/2. In conclusion, the post-exercise biochemical milieu, but not recombinant GH, enhances collagen content and tensile strength of engineered ligaments, in association with mTORC1 and ERK1/2 activation.

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 ß-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.

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.

Biological augmentation and tissue engineering approaches in meniscus surgery.

PURPOSE: The purpose of this review was to evaluate the role of biological augmentation and tissue engineering strategies in meniscus surgery. Although clinical (human), preclinical (animal), and in vitro tissue engineering studies are included here, we have placed additional focus on addressing preclinical and clinical studies reported during the 5-year period used in this review in a systematic fashion while also providing a summary review of some important in vitro tissue engineering findings in the field over the past decade. METHODS: A search was performed on PubMed for original works published from 2009 to March 31, 2014 using the term "meniscus" with all the following terms: "scaffolds," "constructs," "cells," "growth factors," "implant," "tissue engineering," and "regenerative medicine." Inclusion criteria were the following: English-language articles and original clinical, preclinical (in vivo), and in vitro studies of tissue engineering and regenerative medicine application in knee meniscus lesions published from 2009 to March 31, 2014. RESULTS: Three clinical studies and 18 preclinical studies were identified along with 68 tissue engineering in vitro studies. These reports show the increasing promise of biological augmentation and tissue engineering strategies in meniscus surgery. The role of stem cell and growth factor therapy appears to be particularly useful. A review of in vitro tissue engineering studies found a large number of scaffold types to be of promise for meniscus replacement. Limitations include a relatively low number of clinical or preclinical in vivo studies, in addition to the fact there is as yet no report in the literature of a tissue-engineered meniscus construct used clinically. Neither does the literature provide clarity on the optimal meniscus scaffold type or biological augmentation with which meniscus repair or replacement would be best addressed in the future. There is increasing focus on the role of mechanobiology and biomechanical and biochemical cues in this process, however, and it is hoped that this may lead to improvements in this strategy. CONCLUSIONS: There appears to be significant potential for biological augmentation and tissue engineering strategies in meniscus surgery to enhance options for repair and replacement. However, there are still relatively few clinical studies being reported in this regard. There is a strong need for improved translational activities and infrastructure to link the large amounts of in vitro and preclinical biological and tissue engineering data to clinical application. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies.

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) ß1 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 TGFß, 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.