Collagen fibrous scaffolds for sustained delivery of growth factors for meniscal tissue engineering

Aim: To mimic the ultrastructural morphology of the meniscus with nanofiber scaffolds coupled with controlled growth factor delivery to modulate cellular performance for tissue engineering of menisci. Methods: The authors functionalized collagen nanofibers by conjugating heparin to the following growth factors for sustained release: PDGF-BB, TGF-β1 and CTGF. Results: Incorporating growth factors increased human meniscal and synovial cell viability, proliferation and infiltration in vitro, ex vivo and in vivo; upregulated key genes involved in meniscal extracellular matrix synthesis; and enhanced generation of meniscus-like tissue. Conclusion: The authors' results indicate that functionalizing collagen nanofibers can create a cell-favorable micro- and nanoenvironment and can serve as a system for sustained release of bioactive factors.

3D bioprinting for meniscus tissue engineering: a review of key components, recent developments and future opportunities

3D bioprinting has the potential to transform the field of regenerative medicine as it enables the precise spatial patterning of biomaterials, cells and biomolecules to produce engineered tissues. Although numerous tissue engineering strategies have been developed for meniscal repair, the field has yet to realize an implant capable of completely regenerating the tissue. This paper first summarized existing meniscal repair strategies, highlighting the importance of engineering biomimetic implants for successful meniscal regeneration. Next, we reviewed how developments in 3D (bio)printing are accelerating the engineering of functional meniscal tissues and the development of implants targeting damaged or diseased menisci. Some of the opportunities and challenges associated with use of 3D bioprinting for meniscal tissue engineering are identified. Finally, we discussed key emerging research areas with the capacity to enhance the bioprinting of meniscal grafts.

The Relationship Between Discoid Meniscus and Articular Cartilage Thickness: A Quantitative Observational Study With MRI

Background: Several cadaveric imaging studies have demonstrated that the articular cartilage thickness on the tibial plateau varies depending on coverage by native meniscal tissue. These differences are thought to partially contribute to the rates of cartilage degeneration and development of osteoarthritis after meniscectomy. Because there is greater tibial plateau coverage with meniscal tissue in the setting of a discoid meniscus, these findings may also have implications for the long-term health of the knee after saucerization of a torn discoid meniscus. Purpose: To evaluate the relationship between lateral compartment articular cartilage thickness and the presence or absence of a discoid meniscus. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Included in the study were 25 patients younger than 40 years of age who had undergone a 1.5-T or 3-T knee magnetic resonance imaging (MRI) between 2010 and 2016 at a single institution and had an intact, lateral discoid meniscus. Only patients with an otherwise asymptomatic lateral compartment were included. The authors then identified 35 age-matched controls with a nondiscoid, intact lateral meniscus who underwent knee MRI at the same institution and during the same period. The articular cartilage thicknesses in 6 zones of the lateral femoral condyle (LFC) and lateral tibial plateau (LTP) were measured for each patient by 2 musculoskeletal radiologists, and the mean thicknesses were compared between the study and control groups. Results: The average age at MRI was 22.63 years (range, 8.30-35.90 years) for the discoid group and 20.93 years (range, 8.43-34.99 years) for the nondiscoid group. The nondiscoid group had significantly greater mean articular cartilage thickness in all 6 zones of the LTP ( P < .05 for all). When comparing the zones of the LFC, there was no significant difference in the mean thickness in any zone between the 2 groups. Conclusion: Patients with discoid menisci had thinner baseline articular cartilage thickness in the LTP compared with those patients without discoid menisci.

Evaluating the Efficacy of Combined P188 Treatment and Surgical Intervention in Preventing Post-Traumatic Osteoarthritis Following a Traumatic Knee Injury

Previous studies have shown that reconstructive surgery alone following injury to the anterior cruciate ligament (ACL) does not prevent the development of post-traumatic osteoarthritis (PTOA). Poloxamer 188 (P188) has been shown to prevent cell death following trauma in both articular cartilage and meniscal tissue. This study aims to test the efficacy of single or multiple administrations of P188 in conjunction with reconstructive surgery to help prevent or delay the onset of the disease. Thirty skeletally mature rabbits underwent closed-joint trauma that resulted in ACL rupture and meniscal damage and were randomly assigned to one of four treatment groups with varying doses of P188. ACL reconstruction was then performed using an autograft from the semitendinosus tendon. Animals were euthanized 1-month following trauma, meniscal tissue was assessed for changes in morphology, mechanical properties, and proteoglycan content. Femurs and tibias were scanned using microcomputed tomography to determine changes in bone quality, architecture, and osteophyte formation. The medial meniscus experienced more damage and a decrease in the instantaneous modulus regardless of treatment group, while P188 treatment tended to limit degenerative changes in the lateral meniscus. Both lateral and medial menisci had documented decreases in the equilibrium modulus and inconsistent changes in proteoglycan content. Minimal changes were documented in the tibias and femurs, with the only significant change being the formation of osteophytes in both bones regardless of treatment group. The data suggest that P188 was able to limit some degenerative changes in the meniscus associated with PTOA and may warrant future studies.

Collagen orientation probed by polarized Raman spectra can serve as differential diagnosis indicator between different grades of meniscus degeneration

The purpose of the present study was to analyze normal and degenerated menisci with Raman methodology on thin sections of formalin fixed paraffin embedding tissues and to correlate the Raman findings with the grade of meniscus degeneration. Menisci (n = 27) were removed from human knee joints after total knee replacement or meniscectomy. Following routine histopathological analysis to determine the grade of meniscal lesions obtained from healthy and degenerated formaline fixed paraffin embedded (FFPE) meniscal sections, Raman polarization approach was applied to evaluate the orientation of collagen fibrils in different levels of the same 5 μm thick FFPE meniscal tissue sections, used for histopathological assessment. We collected Raman spectra in two different polarization geometries, v-HH and v-VV, and calculated the mean value of the v-HH/v-VV intensity ratio of two Raman bands, sensitive and non-sensitive to the molecular orientation. The collagen specific amide I band at 1665 cm−1, has the higher sensitivity dependence on the Raman polarization. The mean values of ratio v-HH/v-VV of the 1665 cm−1 peak intensity was significantly higher in healthy, mean ± SD: 2.56 ± 0.46, compared to degenerated menisci, mean ± SD: 1.85 ± 0.42 (p = 0.0014). The mean values of v-HH/v-VV intensity ratio were 2.18 and 1.50 for low and high degenerated menisci, respectively (p < 0.0001). The difference of peak intensities in the two laser polarizations is decreased in the degenerated meniscus; this difference is diminishing as the degeneration increases. The v-HH/v-VV ratio was also of significant difference in low as compared to control and high grade meniscus lesions (p = 0.036 and p < 0.0001, respectively) offering valuable information for the approach of its biology and function. In the present study we showed that the 5 μm thick sections can be used for Raman analysis of meniscal tissue with great reliability, in terms of sensitivity, specificity, false-negative and false-positive results. Our data introduce the interesting hypothesis that compact portable Raman microscopy on tissue sections can be used intra-operatively for fast diagnosis and hence, accurate procedure design in the operating room.

Ultrasound-Guided Meniscal Injection of Autologous Growth Factors: A Brief Report

Meniscal degeneration is a common finding even in young patients’ knees, and it is regarded as a predictor for the onset of early osteoarthritis (OA). When symptomatic, it represents a challenge since arthroscopic surgery provides unpredictable results: recent evidence has shown that partial meniscectomy is not better than conservative management up to 2 years of follow-up, and the removal of meniscal tissue may accelerate OA progression toward OA. Intra-articular injection of corticosteroids or hyaluronic acid may help in providing temporary symptomatic relief, but no influence should be expected on the quality of the meniscal tissue. Biologic agents have been adopted to treat a variety of degenerative musculoskeletal pathologies, and the use of platelet-derived growth factors (GFs) has become routine. Preclinical studies have documented that platelet-derived GFs may play a beneficial role in stimulating meniscal repair and regeneration by triggering anabolic pathways and stimulating local mesenchymal stem cells from synovium. Furthermore, also mechanical stimulation (e.g., arthroscopic trephination or percutaneous needling) in the red-red or red-white zone may further promote tissue healing. The purpose of the present brief report is to describe the clinical outcomes at 18 months’ follow-up in a cohort of patients affected by symptomatic medial meniscus degeneration and treated by percutaneous needling plus intra- and perimeniscal injection of autologous conditioned plasma (ACP). The procedure was shown to be safe and provided significant pain reduction and improvement in subjective scores. This treatment option deserves further investigation in a comparative setting, to establish whether it could offer advantage over isolated intra-articular injections.

Localized Pigmented Villonodular Synovitis Originating from the Lateral Meniscus in a 17-year-old: Case Report and Literature Review of Meniscal-Associated Localized PVNS

Tenosynovial giant cell tumors (TSGCT) are benign tumors originating from the synovial joint, bursa, or tendon sheath. Localized pigmented villonodular synovitis (PVNS), a subtype of TSGCT, commonly affects the hands and feet and has also been reported in the literature in the knee joint. There is sparse literature on localized PVNS arising specifically from meniscal tissue. We present a case report of a 17-year- old male with symptoms and MRI findings consistent with a lateral meniscus tear. Intraoperatively, the patient was found to have a mass originating from the torn meniscal tissue, which was confirmed by pathology to be a TSGCT. We performed a literature review of intra-articular localized PVNS within the knee presenting as a meniscal tear.

Meniscal Regenerative Scaffolds Based on Biopolymers and Polymers: Recent Status and Applications

Knee menisci are structurally complex components that preserve appropriate biomechanics of the knee. Meniscal tissue is susceptible to injury and cannot heal spontaneously from most pathologies, especially considering the limited regenerative capacity of the inner avascular region. Conventional clinical treatments span from conservative therapy to meniscus implantation, all with limitations. There have been advances in meniscal tissue engineering and regenerative medicine in terms of potential combinations of polymeric biomaterials, endogenous cells and stimuli, resulting in innovative strategies. Recently, polymeric scaffolds have provided researchers with a powerful instrument to rationally support the requirements for meniscal tissue regeneration, ranging from an ideal architecture to biocompatibility and bioactivity. However, multiple challenges involving the anisotropic structure, sophisticated regenerative process, and challenging healing environment of the meniscus still create barriers to clinical application. Advances in scaffold manufacturing technology, temporal regulation of molecular signaling and investigation of host immunoresponses to scaffolds in tissue engineering provide alternative strategies, and studies have shed light on this field. Accordingly, this review aims to summarize the current polymers used to fabricate meniscal scaffolds and their applications in vivo and in vitro to evaluate their potential utility in meniscal tissue engineering. Recent progress on combinations of two or more types of polymers is described, with a focus on advanced strategies associated with technologies and immune compatibility and tunability. Finally, we discuss the current challenges and future prospects for regenerating injured meniscal tissues.

Autologous Minimally Invasive Cell-Based Therapy for Meniscal and Anterior Cruciate Ligament Regeneration

The meniscus is a fibrocartilaginous tissue that acts as a “shock absorber,” along with performing functions such as stabilization and lubrication of the joint, proprioception, and load distribution. Sudden twisting movements during weight bearing or trauma can cause injury to the menisci, which leads to symptoms such as pain, swelling, and difficulty in performing movements, among others. Conventional pharmacological and surgical treatments are effective in treating the condition; however, do not result in regeneration of healthy tissues. In this report, we highlight the role of cell-based therapy in the management of medial and lateral meniscal and anterior cruciate ligament tears in a patient who was unwilling to undergo surgical treatment. We injected autologous mesenchymal stem cells obtained from the bone marrow and adipose tissue and platelet-rich plasma into the joint of the patient at the area of injury, as well as intravenously. The results of our study corroborate with those previously reported in the literature regarding the improvement in clinical parameters and regeneration of meniscal tissue and ligament. Thus, based on previous literature and improvements noticed in our patient, cell-based therapy can be considered a safe and effective therapeutic modality in the treatment of meniscal tears and cruciate ligament injury.

The critical role of Hedgehog-responsive mesenchymal progenitors in meniscus development and injury repair

Meniscal tears are associated with a high risk of osteoarthritis but currently have no disease-modifying therapies. Using a Gli1 reporter line, we found that Gli1+ cells contribute to the development of meniscus horns from 2 weeks of age. In adult mice, Gli1+ cells resided at the superficial layer of meniscus and expressed known mesenchymal progenitor markers. In culture, meniscal Gli1+ cells possessed high progenitor activities under the control of Hh signal. Meniscus injury at the anterior horn induced a quick expansion of Gli1-lineage cells. Normally, meniscal tissue healed slowly, leading to cartilage degeneration. Ablation of Gli1+ cells further hindered this repair process. Strikingly, intra-articular injection of Gli1+ meniscal cells or an Hh agonist right after injury accelerated the bridging of the interrupted ends and attenuated signs of osteoarthritis. Taken together, our work identified a novel progenitor population in meniscus and proposes a new treatment for repairing injured meniscus and preventing osteoarthritis.