Cartilage Penetration Research Articles

Bioengineered chondrocyte membrane-camouflaged anti-ferroptotic drug-loaded liposomes: A highly effective cartilage-targeted drug delivery system for osteoarthritis treatment

Osteoarthritis (OA) is a chronic degenerative joint disorder that severely impacts patients’ quality of life. Despite various drug treatment strategies, achieving effective therapeutic outcomes remains challenging due to the joint’s unique structure, which results in rapid drug clearance through synovial fluid and the dense, avascular cartilage matrix. To address this issue, we developed an innovative nanoplatform utilizing biomimetic cell membrane-coating technology. This bioengineered chondrocyte membrane-camouflaged, anti-ferroptotic, drug-loaded system enhances cartilage penetration, prolongs drug retention, and provides targeted therapy. As a nanovehicle, it targets chondrocytes through membrane fusion, allowing rapid penetration and mitigating OA progression. In vitro experiments show that this nanocarrier alleviates iron homeostasis imbalance and suppresses lipid peroxidation, helping ameliorate metabolic disorders in chondrocytes and addressing multiple pathological processes triggered by ferroptosis. In vivo results further suggest that this “Trojan Horse” strategy extends drug retention in joints and improves therapeutic efficacy. This study presents a potential universal nanoplatform comprising bioengineered chondrocyte membrane-coated liposomes for highly effective cartilage-targeted drug delivery in OA treatment.

Multifunctional polymeric nanocapsules with enhanced cartilage penetration and retention for osteoarthritis treatment

Osteoarthritis (OA) is a prevalent joint disease characterized by cartilage degeneration and subchondral bone homeostasis imbalance. Effective topical OA therapy is challenging, as therapeutic drugs often suffer from insufficient penetration and rapid clearance. We develop miniature polydopamine (PDA) nanocapsules (sub-60 nm), which are conjugated with collagen-binding polypeptide (CBP) and loaded with an anabolic drug (i.e., parathyroid hormone 1–34, PTH 1–34) for efficient OA treatment. Such multifunctional polymeric nanocapsules, denoted as PDA@CBP-PTH, possess deformability when interacting with the dense collagen fiber networks, enabling the efficient penetration into 1 mm cartilage in 4 h and prolonged retention within the joints up to 28 days. Moreover, PDA@CBP-PTH nanocapsules exhibit excellent reactive oxygen species scavenging property in chondrocytes and enhance the anabolism in subchondral bone. The nanosystem, as dual-mode treatment for OA, demonstrates rapid penetration, long-lasting effects, and combinational therapeutic impact, paving the way for reversing the progression of OA for joint health care.

Self-Reinforced MOF-Based Nanogel Alleviates Osteoarthritis by Long-Acting Drug Release.

Intra-articular injection of drugs is an effective strategy for osteoarthritis (OA) treatment. However, the complex microenvironment and limited joint space result in rapid clearance of drugs. Herein, a nanogel-based strategy is proposed for prolonged drug delivery and microenvironment remodeling. Nanogel is constructed through the functionalization of hyaluronic acid (HA) by amide reaction on the surface of Kartogenin (KGN)-loaded zeolitic imidazolate framework-8 (denoted as KZIF@HA). Leveraging the inherent hydrophilicity of HA, KZIF@HA spontaneously forms nanogels, ensuring extended drug release in the OA microenvironment. KZIF@HA exhibits sustained drug release over one month, with low leakage risk from the joint cavity compared to KZIF, enhanced cartilage penetration, and reparative effects on chondrocytes. Notably, KGN released from KZIF@HA serves to promote extracellular matrix (ECM) secretion for hyaline cartilage regeneration. Zn2+ release reverses OA progression by promoting M2 macrophage polarization to establish an anti-inflammatory microenvironment. Ultimately, KZIF@HA facilitates cartilage regeneration and OA alleviation within three months. Transcriptome sequencing validates that KZIF@HA stimulates the polarization of M2 macrophages and secretes IL-10 to inhibit the JNK and ERK pathways, promoting chondrocytes recovery and enhancing ECM remodeling. This pioneering nanogel system offers new therapeutic opportunities for sustained drug release, presenting a significant stride in OA treatment strategies.

Zwitterionic polymer-dexamethasone conjugates penetrate and protect cartilage from inflammation

Improving the pharmacokinetics of intra-articularly injected therapeutics is a major challenge in treating joint disease. Small molecules and biologics are often cleared from the joint within hours, which greatly reduces their therapeutic efficacy. Furthermore, they are often injected at high doses, which can lead to local cytotoxicity and systemic side effects. In this study, we present modular polymer-drug conjugates of zwitterionic poly(carboxybetaine acrylamide) (pCBAA) and the anti-inflammatory glucocorticoid dexamethasone (DEX) to create cartilage-targeted carriers with slow-release kinetics. pCBAA polymers showed excellent cartilage penetration (full thickness in 1 h) and retention (>50 % after 2 weeks of washing). DEX was loaded onto the pCBAA polymer by employing two different DEX-bearing comonomers to produce pCBAA-co-DEX conjugates with different release kinetics. The slow-releasing conjugate showed zero-order release kinetics in PBS over 70 days. The conjugates elicited no oxidative stress on chondrocytes compared to dose-matched free DEX and protected bovine cartilage explants from the inflammatory response after treatment with IL-1β. By combining cartilage targeting and sustained drug release properties, the pCBAA-co-DEX conjugates solve many issues of today's intra-articular therapeutics, which could ultimately enable better long-term clinical outcomes with fewer side effects.

Reproducible Synthesis of Biocompatible Albumin Nanoparticles Designed for Intra-articular Administration of Celecoxib to Treat Osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis, with intra-articular (IA) delivery of therapeutics being the current best option to treat pain and inflammation. However, IA delivery is challenging due to the rapid clearance of therapeutics from the joint and the need for repeated injections. Thus, there is a need for long-acting delivery systems that increase the drug retention time in joints with the capacity to penetrate OA cartilage. As pharmaceutical utility also demands that this is achieved using biocompatible materials that provide colloidal stability, our aim was to develop a nanoparticle (NP) delivery system loaded with the COX-2 inhibitor celecoxib that can meet these criteria. We devised a reproducible and economical method to synthesize the colloidally stable albumin NPs loaded with celecoxib without the use of any of the following conditions: high temperatures at which albumin denaturation occurs, polymer coatings, oils, Class 1/2 solvents, and chemical protein cross-linkers. The spherical NP suspensions were biocompatible, monodisperse with average diameters of 72 nm (ideal for OA cartilage penetration), and they were stable over 6 months at 4 °C. Moreover, the NPs loaded celecoxib at higher levels than those required for the therapeutic response in arthritic joints. For these reasons, they are the first of their kind. Labeled NPs were internalized by primary human articular chondrocytes cultured from the knee joints of OA patients. The NPs reduced the concentration of inflammatory mediator prostaglandin E2 released by the primaries, an indication of retained bioactivity following NP synthesis. Similar results were observed in lipopolysaccharide-stimulated human THP-1 monocytes. The IA administration of these NPs is expected to avoid side-effects associated with oral administration of celecoxib and to maintain a high local concentration in the knee joint over a sustained period. They are now ready for evaluation by IA administration in animal models of OA.

Inflammation‐Regulated Auto Aggregated Hydrogel Microspheres Via Anchoring Cartilage Deep Matrix for Genes Delivery

AbstractThe high density structure of cartilage matrix negative charge seriously hinders the penetration and enrichment of drugs/genes into cartilage tissue. In this study, hexachlorocyclotriphosphonitrile is used as the core to prepare self‐polymerized phosphorus dendrimers with inflammatory reaction through substitution and condensation reaction. The vector can achieve efficient penetration of the damaged articular cartilage (slightly acidic condition) and effective anchoring of cartilage matrix (normal physiological condition) through the size effect under inflammatory response. Meanwhile, as a gene “delivery library,” G1‐NC5.HCl@siRNA is gradually released with microspheres degrading; the long‐term silencing of specific genes is realized. Further, G1‐NC5.HCl@siRNA is loaded into the hydrogel microspheres by ionic bond coordination and microfluidic techniques to improve the residency effect of G1‐NC5.HCl@siRNA in the joint cavity. The results of cartilage in vitro and in vivo experiments show that the gene complex has a better penetration effect at pH = 6.6, and the cartilage penetration effect decreases at pH = 7.6, which can effectively anchor in the cartilage matrix site for continuous drug delivery. Further, the composite hydrogel microspheres significantly improve the degeneration of osteoarthritis (OA) cartilage and promote cartilage regeneration. Therefore, the self‐polymerized hydrogel microsphere delivery system with inflammatory response is a promising penetrant/anchoring carrier system for OA treatment.

Computational Control Strategy for Reducing Medial Compartment Load in Knee Bracing with Embedded Actuator

Medial unloader braces represent a primary noninvasive approach for alleviating knee pain. However, conventional valgus unloader braces, while reducing load on the medial compartment, inadvertently increase load on the lateral compartment through rotation from adduction to abduction. This phenomenon significantly elevates the risk of damage to the lateral compartment. To address this issue, we introduce a novel embedded actuation mechanism that unloads the knee using a pioneering computational procedure. By considering the knee osteoarthritis condition, we propose the calculation of the adduction knee angle and cartilage penetration depth as surrogate parameters for assessing knee pain. Accordingly, the newly developed unloader brace redistributes the load by precisely correcting the abduction angle. Additionally, we determine the maximum required torque for effectively tracking the desired abduction angle. Then, the saturated torque through the robust control method is applied in the presence of interaction force uncertainty between the orthosis and the user. A very small femur rotation change (1.7°) from adduction to abduction in the frontal plane is adequate to significantly reduce the medial contact force (around 886 N). The required robust external abduction torque is determined to be 27.6 Nm. The result shows that the novel procedure and brace prevent excessive overloading of the lateral compartment while it unloads the medial compartment sufficiently. This innovative approach offers significant potential for optimizing unloader brace design and enhancing the management of knee osteoarthritis.

Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial

Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043—a derivative of angiopoietin-like 3 (ANGPTL3)—as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin α5β1 on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial (NCT02491281; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial (NCT04864392) in patients with knee OA.

Polymeric Nanoparticles for Drug Delivery in Osteoarthritis.

Osteoarthritis (OA) is a degenerative musculoskeletal disorder affecting the whole synovial joint and globally impacts more than one in five individuals aged 40 and over, representing a huge socioeconomic burden. Drug penetration into and retention within the joints are major challenges in the development of regenerative therapies for OA. During the recent years, polymeric nanoparticles (PNPs) have emerged as promising drug carrier candidates due to their biodegradable properties, nanoscale structure, functional versatility, and reproducible manufacturing, which makes them particularly attractive for cartilage penetration and joint retention. In this review, we discuss the current development state of natural and synthetic PNPs for drug delivery and OA treatment. Evidence from in vitro and pre-clinical in vivo studies is used to show how disease pathology and key cellular pathways of joint inflammation are modulated by these nanoparticle-based therapies. Furthermore, we compare the biodegradability and surface modification of these nanocarriers in relation to the drug release profile and tissue targeting. Finally, the main challenges for nanoparticle delivery to the cartilage are discussed, as a function of disease state and physicochemical properties of PNPs such as size and surface charge.

Anchor Arthropathy Caused by Cartilage Penetration: An Approach to Revision Hip Arthroscopy With Removal of Problematic Anchors

Hip arthroscopy has been proven to effectively treat labral tears in the setting of femoroacetabular impingement. Anchors used for this treatment have constantly evolved and improved to ensure safety and minimal invasion. However, acetabular drilling and anchor placement are technically challenging due to the concavity of the acetabular articular surface, limited angles for anchor insertion, and finite bone availability in the anterior and posterior column. Inadequate technique can result in protruding anchors, which may lead to full-thickness articular cartilage damage, manifesting in pain, mechanical symptoms, and impaired function. This Technical Note demonstrates arthroscopic removal of protruding anchors and management of the iatrogenic grade IV cartilage damage. In this description, the technical pearls and pitfalls of acetabular anchor placement to treat labral pathology are presented along with the aforementioned technique.

A developed multibody knee model for unloading knee with cartilage penetration depth control.

Unloader knee braces could relieve pain by decreasing the medial knee loading. Particularly for knee osteoarthritis (KOA) patients, this study investigates the relevance of the knee model after identifying the most influential parameter. Since KOA causes the cartilage in a joint to lose its elasticity and thickness, the lack of normal bone-to-bone separation can be painful. We believe that cartilage penetration depth control is an impactful strategy in this research. Moreover, the knee contact force in KOA is fewer than in healthy knees, confirming that the contact force control cannot be a straight factor. Therefore, a biomechanical human knee model is developed, and a generic procedure for dynamic analysis of contact problems in combination with the musculoskeletal model is introduced. The developed model includes the geometric expression of collision curves and an algorithm for determining collision points. This presentation addresses cartilage penetration depth and contact force calculation through nonlinear discontinuous contact law. In view of this, femur and tibia's relative motion is analyzed through the combined collision reactions of cartilage and bone in the knee. In the simulation, maximum penetration depth in a healthy knee is reported to be 0.795 mm, while in a 75% KOA is 0.521 mm, including 0.5 mm cartilage-cartilage contact and 0.021 mm bone-bone contact. The top unloading 852 N is achieved, reducing penetration depth to 0.45 mm, avoiding bone-bone contact. This proposed procedure with low computation gives us a suitable analysis method for designing knee assistive devices.

Injectable Double Positively Charged Hydrogel Microspheres for Targeting-Penetration-Phagocytosis.

The localization and accumulation of drugs in the body determine their therapeutic effects; however, the specific microstructure of damaged tissues hinders drug delivery. Currently, there is a shortage of effective drug carriers to breach these barriers and achieve efficient tissue and cellular delivery of drugs. In this study, an injectable double positively charged functional hydrogel microsphere with "targeting cartilage extracellular matrix", "cartilage penetration", and "cellular phagocytosis" is designed for matching the structural characteristics of joints, addressing the difficulties of drug delivery in joints. The microspheres could be adsorbed on the negatively charged cartilage surface because of their positively charged poly-lysine surface. Furthermore, the internally loaded positively charged polyamidoamine contained kartogenin, which helpedfurther the penetration ofthe cartilage under the guidance of electrical charge. The microspheres couldrelease kartogenin for more than 21 days. Inin vivo experiments, the microspheres effectively improve the efficiency of drug delivery, inhibit the degradation of cartilage matrix and subchondral bone, and delay the development of osteoarthritis. As a double positively charged drug delivery system, the versatile microsphere has great potential for treating osteoarthritis and other diseases.

Bipolar Radiofrequency Ablation Does Not Result in Full-Thickness Articular Cartilage Penetration: An Ex Vivo Bovine Investigation

PurposeTo evaluate the depth of penetration of manufacturer-recommended bipolar radiofrequency (BRF) output in healthy hyaline cartilage.MethodsTwo matched knees from a bovine specimen were harvested for immediate testing. BRF probes were used to treat the articular cartilage in a hydrated noncontact technique employing a 1-mm spacer on patellar, condylar, and trochlear surfaces. Two manufacturer-recommended ablate power settings were evaluated to analyze the effect of varying power outputs on the depth of penetration. Surfaces were randomized and treated with BRF ablate setting 3 (AB-3), 4 (AB-4), or left untreated as a control (12 grids each). Slices were extracted from treatment zones and subjected to fluorescein diacetate and propidium iodide viability stains and analyzed with confocal light microscopy. A general linear model was used to determine whether variables such as ablation setting, cartilage location, and side significantly influenced depth of penetration (DoP) and cartilage thickness (Minitab 19, Chicago, IL). When significance was noted (P < .05), a post hoc-Tukey test was used to investigate specific differences.ResultsAB-3 had a 50.9% lower mean DoP than AB-4 (P = .006). The mean DoP was 237.9 ± 140.6 μm for AB-3 and 484.1 ± 267.0 μm for AB-4. Median DoP values were 243.2 ± 149.5 μm for AB-3, 51.2% lower than the 498.4 ± 286.0 μm for AB-4. The mean maximum DoP for AB-3 was 302.4 ± 167.8 μm, 50.6% lower than AB-4 value of 611.6 ± 299.1 μm. Analysis of the cartilage thickness confirmed there was no difference in overall cartilage thickness used for AB-3 versus AB-4 testing (P = .953).ConclusionsThe RF probe ablate power setting AB-3 demonstrated significantly less articular cartilage depth of penetration than the AB-4 setting in a healthy bovine model.Clinical RelevanceDebridement of chondral lesions with plasma BRF is of clinical interest. The presented study adds basic science information for those considering performing this technique.

Association between cancer surface area and histopathological parameters of laryngeal squamous cell carcinoma in total laryngectomy specimens

Background/Aim. Numerous histopathological parameters, such as cartilage penetration, perineural and lymphovascular invasion, presence of metastatic tissue in regional lymph nodes (LNs), extranodal extension (ENE) of nodal metastases, as well as the presence of cancer tissue on resection borders, are all important factors influencing survival in patients with laryngeal squamous cell carcinoma (LSCC). The aim of the study was to determine if there is an association between cancer surface area (CSA) and these histopathological characteristics. The presence of ENE of metastatic tissue in regional LNs was also investigated. Methods. In a retrospective study, one hundred and forty cases of LSCC were revised and processed after total laryngectomy. The cases were found in the archives of the Histopathology Laboratory of the Clinic for Otorhinolaryngology and Maxillofacial Surgery, University Clinical Center of Serbia. Results. A significant difference was found in CSA depending on cancer penetration into the thyroid cartilage, perineural invasion, and positive resection margins. Cancers with larger CSA were more common in the advanced T stage. Metastases were found in 36 out of 72 (50%) neck LN samples submitted for evaluation. The difference in CSA was also found depending on the presence of metastatic tissue in regional LNs. ENE was present in 69.4% of involved LNs, and it was more frequent in LNs 3 cm in size or larger. Conclusion. There is a significant difference in CSA depending on the presence of cartilage penetration, perineural invasion, presence of cancer tissue on resection borders, and presence of metastases in regional LNs. Larger cancers tend to be of a higher T stage. ENE is more common in LNs 3 cm in size or larger.

Crown-Cut Endobronchial Ultrasound Guided Transbronchial Aspiration Needle: First Real-World Experiences.

Advancements in personalized medicine have increased the demand for quantity and preservation of tissue architecture of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples. These demands may be addressed by the SonoTip TopGain® needle, which has a 3-point crown-cut design that contrasts with the standard single bevel design of the ViziShot 2®. The objective was to compare the SonoTip TopGain® and ViziShot 2® needles by considering biopsy sample characteristics, diagnostic accuracy, and patient safety. The primary endpoint of the study was the number of high-power fields (HPFs) in the center of the formalin-fixed paraffin-embedded cell block per sample. The lymph node with the highest probability for malignant infiltration based on size and sonographic appearance was chosen as the target lymph node for 20 patients. The same lymph node in each patient was sampled using both the ViziShot 2® and SonoTip TopGain® needles. The samples were measured, sliced, and analyzed by a pathologist. Sixteen patients were biopsied with both needles. Four patients could not be biopsied with the SonoTip TopGain® needle since it could not penetrate cartilage or be repositioned to bypass cartilage. HPFs and sample dimensions were significantly greater in the patients where sampling with the SonoTip TopGain® needle was possible (p = 0.007 and p = 0.005, respectively). Diagnostic accuracy and safety profiles were comparable. Significantly more material can be sampled using the SonoTip TopGain® needle when cartilage penetration can be avoided. This improves the yield for molecular workup in the era of personalized medicine.

Reversing the surface charge of MSC-derived small extracellular vesicles by εPL-PEG-DSPE for enhanced osteoarthritis treatment.

Mesenchymal stem cell‐derived small extracellular vesicles (MSC‐sEVs) possess a great therapeutical potential for osteoarthritis (OA) treatment. However, the steric and electrostatic hindrance of cartilage matrix leads to very limited distribution of MSC‐sEVs in cartilage and low bioavailability of MSC‐sEVs after intra‐articular injection. To overcome this, a strategy to reverse the surface charge of MSC‐sEVs by modifying the MSC‐sEVs with a novel cationic amphiphilic macromolecule namely ε‐polylysine‐polyethylene‐distearyl phosphatidylethanolamine (PPD) was developed in this study. Through incubation with 100 μg/ml PPD, positively charged MSC‐sEVs (PPD‐sEVs) were obtained, and the modification process showed nearly no disturbance to the integrity and contents of sEVs and exhibited good stability under the interference of anionic macromolecules. A more effective cellular uptake and homeostasis modulation ability of PPD‐sEVs than unmodified MSC‐sEVs to chondrocytes was demonstrated. More importantly, PPD‐sEVs demonstrated significantly enhanced cartilage uptake, cartilage penetration, and joint retention capacity as compared to MSC‐sEVs. Intra‐articular injection of PPD‐sEVs into a mouse OA model showed significantly improved bioavailability than MSC‐sEVs, which resulted in enhanced therapeutic efficacy with reduced injection frequency. In general, this study provides a facile and effective strategy to improve the intra‐articular bioavailability of MSC‐sEVs and has a great potential to accelerate the clinical practice of MSC‐sEVs based OA therapy.

Assessment of cartilage invasion in case of laryngeal cancer by means of longitudinal sectioning for histopathology - Clinical implications.

The aim of the study was to assess the accuracy of radiological diagnosis of laryngeal cartilage infiltration by histopathological examination of laryngeal specimen after total laryngectomy. Despite the development of new medical technologies and significant clinical advances allowing early diagnosis and treatment of laryngeal cancer, mortality is still on the rise. Neoplastic infiltration of the laryngeal cartilages is the most common source of error in the assessment of cancer staging. Furthermore, cartilage invasion is listed as a contraindication to partial surgical techniques as well as radiotherapy. The study was carried out on 21 larynges following total laryngectomy. Before taking the decision to perform surgery, high-resolution CT scans were performed in all cases. An extended histopathological examination was conducted using a unique vertical cross-section of the whole larynx. Pathology reported 2 cases of arytenoid cartilage invasion, 5 cases of cricoid cartilage invasion, 12 cases of thyroid cartilage penetration, 1 case of internal cortex invasion and 9 cases of extra-laryngeal spread. CT imaging identified 8 of 13 cases (61.5%) of pathologically proven invasion of thyroid cartilage and only 2 cases (2/9, 22%) of extra-laryngeal spread. According to CT results, arytenoid cartilage invasion was correctly identified in 2 cases, cricoid cartilage invasion in 4 (4/5, 80%). The positive predictive values for thyroid, cricoid and arytenoid cartilage invasion and penetration were 80%, 66.7% and 50%, respectively. In case of pre-laryngeal spread the positive predictive value was 100%. Despite increasingly advanced methods involved in the diagnosis of laryngeal cancer, many discrepancies may be observed between the radiological and histopathological assessments. CT imaging has limitations especially in thyroid cartilage penetration and extra-laryngeal spread assessment in advanced laryngeal cancer cases. An extended histopathological examination, involving vertical cross-sections of the whole larynx is a very precise study that allows a precise determination of local cancer staging (T).

Stabilization of T2 relaxation and magnetization transfer in cartilage explants by immersion in perfluorocarbon liquid.

Magnetic resonance imaging of ex vivo cartilage measures parameters such as T2 and magnetization transfer ratio (MTR), which reflect structural changes associated with osteoarthritis. Samples are often immersed in aqueous solutions to prevent dehydration and to to improve susceptibility matching. This study sought to determine the extent to which T2 and MTR changes are attributable to immersion alone and to identify immersion conditions to minimize this confounding factor. T2 and MTR were measured before and after immersion for up to 24 hours at 4°C. Bovine nasal and articular cartilage and human articular cartilage were studied. Experimental groups included undisturbed immersion in Fluorinert FC-770, a susceptibility-matched, hydrophobic liquid with minimal tissue penetration, and immersion in Fluorinert, Dulbecco's phosphate-buffered saline (DPBS), or saline, with removal from the magnet between scans. 19 F and 1 H-MRI were used to detect cartilage penetration by Fluorinert and swelling, respectively. Saline and DPBS immersion rapidly increased T2 , wet weight and cartilage volume and decreased MTR, suggesting increased water content for all cartilage types. Fluorinert-immersed samples exhibited minimal changes in T2 or MTR. No ingress of Fluorinert was detected after 2 weeks of continuous immersion at 4°C. Ex vivo quantitative MR studies of cartilage may be confounded by the effects of immersion in aqueous solution, which may be comparable to or larger than effects attributed to pathology. These effects may be mitigated by immersion in perfluorocarbon liquids such as Fluorinert FC-770.

Green fluorescent proteins engineered for cartilage-targeted drug delivery: Insights for transport into highly charged avascular tissues

Osteoarthritis (OA), the most common form of arthritis, is a multi-factorial disease that primarily affects cartilage as well as other joint tissues such as subchondral bone. The lack of effective drug delivery, due to the avascular nature of cartilage and the rapid clearance of intra-articularly delivered drugs via the synovium, remains a major challenge in the development of disease modifying drugs for OA. Cationic delivery carriers can significantly enhance the uptake, penetration and retention of drugs in cartilage by interacting with negatively charged matrix proteoglycans. In this study, we used ”supercharged” green fluorescent proteins (GFPs), engineered to have a wide range of net positive charge and surface charge distributions, to characterize the effects of carrier charge on transport into cartilage in isolation of other factors such as carrier size and shape. We quantified the uptake, extent of cartilage penetration and cellular uptake of the GFP variants into living human knee cartilage and bovine cartilage explants. Based on these results, we identified optimal net charges of GFP carriers for potential drug targets located within cartilage extracellular matrix as well as the resident live chondrocytes. These cationic GFPs did not have adverse effects on cartilage in terms of measured cell viability and metabolism, cartilage cell biosynthesis and matrix degradation at doses needed for drug delivery. In addition to quantifying the kinetics of GFP uptake, we developed a predictive mathematical model for transport of the GFP variants that exhibited the highest uptake and penetration into cartilage. This model was further used to predict the transport behavior of GFPs during scale-up to in vivo applications such as intra-articular injection into human knees. The insights gained from this study set the stage for development of cartilage-targeted delivery systems to prevent cartilage degeneration, improve tissue regeneration and reduce inflammation that may cause degradation of other joint tissues affected by OA.

All-Arthroscopic Suture Fixation of Patellar Osteochondritis Dissecans

Osteochondritis dissecans of the knee, despite its cause, is characterized by the impairment of the subchondral bone. Failure of its spontaneous healing makes surgical fixation often necessary. The patella is less affected than other locations in the knee. Its surgical treatment remains a challenge due to the thickness of the lesion and the complex approach of the retropatellar cartilage. Arthroscopy has the theoretical advantage to avoid a possible arthrotomy; however, the retrograde application of fixation materials does not guarantee good fragment compression and may lead to cartilage penetration and damage. The purpose of this Technical Note is to present a reproducible, full arthroscopic suture fixation technique for patellar osteochondritis dissecans lesions. By using the posterior cruciate tibial drill guide, absorbable sutures are passed through the center and the peripheral borders of the lesion resulting in a “spider-parachute-type” fixation with direct fragment compression.