Commitment of human mesenchymal stromal cells towards ACL fibroblast differentiation upon rAAV-mediated FGF-2 and TGF-ß overexpression using pNaSS-grafted PCL films.

Despite various clinical options, human anterior cruciate ligament (ACL) lesions do not fully heal. Biomaterial-guided gene therapy using recombinant adeno-associated virus (rAAV) vectors may improve the intrinsic mechanisms of ACL repair. Here, we examined whether poly(sodium styrene sulfonate)-grafted poly(ε-caprolactone) (pNaSS-grafted PCL) films can deliver rAAV vectors coding for the reparative basic fibroblast growth factor (FGF-2) and transforming growth factor beta (TGF-ß) in human mesenchymal stromal cells (hMSCs) as a source of implantable cells in ACL lesions. Efficient and sustained rAAV-mediated reporter (red fluorescent protein) and therapeutic (FGF-2 and TGF-ß) gene overexpression was achieved in the cells for at least 21 days in particular with pNaSS-grafted PCL films relative to all other conditions (up to 5.2-fold difference). Expression of FGF-2 and TGF-ß mediated by rAAV using PCL films increased the levels of cell proliferation, the DNA contents, and the deposition of proteoglycans and of type-I and -III collagen (up to 2.9-fold difference) over time in the cells with higher levels of transcription factor expression (Mohawk, Scleraxis) (up to 1.9-fold difference), without activation of inflammatory tumor necrosis alpha especially when using pNaSS-grafted PCL films compared with the controls. Overall, the effects mediated by TGF-ß were higher than those promoted by FGF-2, possibly due to higher levels of gene expression achieved upon rAAV gene transfer. This study shows the potential of using functionalized PCL films to apply rAAV vectors for ACL repair.

Functionalized hydrogels as smart gene delivery systems to treat musculoskeletal disorders.

Despite critical advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy based on the delivery of therapeutic genetic sequences has strong value to offer effective, durable options to decisively manage such disorders. Furthermore, scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy, allowing for the spatiotemporal delivery of candidate genes to sites of injury. Among the many scaffolds for musculoskeletal research, hydrogels raised increasing attention in addition to other potent systems (solid, hybrid scaffolds) due to their versatility and competence as drug and cell carriers in tissue engineering and wound dressing. Attractive functionalities of hydrogels for musculoskeletal therapy include their injectability, stimuli-responsiveness, self-healing, and nanocomposition that may further allow to upgrade of them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. Such functionalized hydrogels may also be tuned to successfully transfer therapeutic genes in a minimally invasive manner in order to protect their cargos and allow for their long-term effects. In light of such features, this review focuses on functionalized hydrogels and demonstrates their competence for the treatment of musculoskeletal disorders using gene therapy procedures, from gene therapy principles to hydrogel functionalization methods and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are being discussed in the perspective of translation in patients. STATEMENT OF SIGNIFICANCE: Despite advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy has strong value in offering effective, durable options to decisively manage such disorders. Scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy. Among many scaffolds for musculoskeletal research, hydrogels raised increasing attention. Functionalities including injectability, stimuli-responsiveness, and self-healing, tune them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. This review introduces functionalized hydrogels for musculoskeletal disorder treatment using gene therapy procedures, from gene therapy principles to functionalized hydrogels and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are discussed from the perspective of translation in patients.

Temporal progression of subchondral bone alterations in OA models involving induction of compromised meniscus integrity in mice and rats: A scoping review.

OBJECTIVE: To categorize the temporal progression of subchondral bone alterations induced by compromising meniscus integrity in mouse and rat models of knee osteoarthritis (OA). METHOD: Scoping review of investigations reporting subchondral bone changes with appropriate negative controls in the different mouse and rat models of OA induced by compromising meniscus integrity. RESULTS: The available literature provides appropriate temporal detail on subchondral changes in these models, covering the entire spectrum of OA with an emphasis on early and mid-term time points. Microstructural changes of the subarticular spongiosa are comprehensively described; those of the subchondral bone plate are not. In mouse models, global subchondral bone alterations are unidirectional, involving an advancing sclerosis of the trabecular structure over time. In rats, biphasic subchondral bone alterations begin with an osteopenic degeneration and loss of subchondral trabeculae, progressing to a late sclerosis of the entire subchondral bone. Rat models, independently from the applied technique, relatively faithfully mirror the early bone loss detected in larger animals, and the late subchondral bone sclerosis observed in human advanced OA. CONCLUSION: Mice and rats allow us to study the microstructural consequences of compromising meniscus integrity at high temporal detail. Thickening of the subchondral bone plate, an early loss of thinner subarticular trabecular elements, followed by a subsequent sclerosis of the entire subchondral bone are all important and reliable hallmarks that occur in parallel with the advancing articular cartilage degeneration. Thoughtful decisions on the study design, laterality, selection of controls and volumes of interest are crucial to obtain meaningful data.

A novel entity of massive multifocal osteolyses in the elderly.

Osteolyses are common findings in elderly patients and most frequently represent malignant or locally aggressive bone tumors, infection, inflammatory and endocrine disorders, histiocytoses, and rare diseases such as Gorham-Stout syndrome. We here report on a novel entity of massive multifocal osteolyses in both shoulders, the right hip and left knee joint and the dens of an 83-year-old patient not relatable to any previously known etiopathology of bone disorders. The soft tissue mass is of myxoid stroma with an unspecific granulomatous inflammatory process, aggressively destroying extensive cortical and cancellous bone segments and encroaching on articulating bones in diarthrodial large joints. Radiological, nuclear medical, serological, histological, and immunohistochemical analyses were incapable of further classifying the disease pattern within the existing scheme of pathology. Quantitative polymerase chain reaction and next generation sequencing revealed that mutations are not suggestive of any known hereditary or acquired bone disease. Possible treatment options include radionuclide therapy for pain palliation and percutaneous radiation to arrest bone resorption while surgical treatment is inevitable for pathological fractures. This case study shall increase the awareness of the musculoskeletal community and motivate to collect further information on this rare but mutilating disorder.

Locally Directed Recombinant Adeno- Associated Virus-Mediated IGF-1 Gene Therapy Enhances Osteochondral Repair and Counteracts Early Osteoarthritis In Vivo.

BACKGROUND: Restoration of osteochondral defects is critical, because osteoarthritis (OA) can arise. HYPOTHESIS: Overexpression of insulin-like growth factor 1 (IGF-1) via recombinant adeno-associated viral (rAAV) vectors (rAAV-IGF-1) would improve osteochondral repair and reduce parameters of early perifocal OA in sheep after 6 months in vivo. STUDY DESIGN: Controlled laboratory study. METHODS: Osteochondral defects were created in the femoral trochlea of adult sheep and treated with rAAV-IGF-1 or rAAV-lacZ (control) (24 defects in 6 knees per group). After 6 months in vivo, osteochondral repair and perifocal OA were assessed by well-established macroscopic, histological, and immunohistochemical scoring systems as well as biochemical and micro-computed tomography evaluations. RESULTS: Application of rAAV-IGF-1 led to prolonged (6 months) IGF-1 overexpression without adverse effects, maintaining a significantly superior overall cartilage repair, together with significantly improved defect filling, extracellular matrix staining, cellular morphology, and surface architecture compared with rAAV-lacZ. Expression of type II collagen significantly increased and that of type I collagen significantly decreased. Subchondral bone repair and tidemark formation were significantly improved, and subchondral bone plate thickness and subarticular spongiosa mineral density returned to normal. The OA parameters of perifocal structure, cell cloning, and matrix staining were significantly better preserved upon rAAV-IGF-1 compared with rAAV-lacZ. Novel mechanistic associations between parameters of osteochondral repair and OA were identified. CONCLUSION: Local rAAV-mediated IGF-1 overexpression enhanced osteochondral repair and ameliorated parameters of perifocal early OA. CLINICAL RELEVANCE: IGF-1 gene therapy may be beneficial in repair of focal osteochondral defects and prevention of perifocal OA.

Modulation of early osteoarthritis by tibiofemoral re-alignment in sheep.

OBJECTIVE: To investigate whether tibiofemoral alignment influences early knee osteoarthritis (OA). We hypothesized that varus overload exacerbates early degenerative osteochondral changes, and that valgus underload diminishes early OA. METHOD: Normal, over- and underload were induced by altering alignment via high tibial osteotomy in adult sheep (n = 8 each). Simultaneously, OA was induced by partial medial anterior meniscectomy. At 6 weeks postoperatively, OA was examined in five individual subregions of the medial tibial plateau using Kellgren-Lawrence grading, quantification of macroscopic OA, semiquantitative histopathological OA and immunohistochemical type-II collagen, ADAMTS-5, and MMP-13 scoring, biochemical determination of DNA and proteoglycan contents, and micro-computed tomographic evaluation of the subchondral bone. RESULTS: Multivariate analyses revealed that OA cartilaginous changes had a temporal priority over subchondral bone changes. Underload inhibited early cartilage degeneration in a characteristic topographic pattern (P ≥ 0.0983 vs. normal), in particular below the meniscal damage, avoided alterations of the subarticular spongiosa (P ≥ 0.162 vs. normal), and prevented the disturbance of otherwise normal osteochondral correlations. Overload induced early alterations of the subchondral bone plate microstructure towards osteopenia, including significantly decreased percent bone volume and increased bone surface-to-volume ratio (all P ≤ 0.0359 vs. normal). CONCLUSION: The data provide high-resolution evidence that tibiofemoral alignment modulates early OA induced by a medial meniscus injury in adult sheep. Since underload inhibits early OA, these data also support the clinical value of strategies to reduce the load in an affected knee compartment to possibly decelerate structural OA progression.

Subchondral bone remodeling patterns in larger animal models of meniscal injuries inducing knee osteoarthritis - a systematic review.

PURPOSE: Elucidating subchondral bone remodeling in preclinical models of traumatic meniscus injury may address clinically relevant questions about determinants of knee osteoarthritis (OA). METHODS: Studies on subchondral bone remodeling in larger animal models applying meniscal injuries as standardizing entity were systematically analyzed. Of the identified 5367 papers reporting total or partial meniscectomy, meniscal transection or destabilization, 0.4% (in guinea pigs, rabbits, dogs, minipigs, sheep) remained eligible. RESULTS: Only early or mid-term time points were available. Larger joint sizes allow reporting higher topographical details. The most frequently reported parameters were BV/TV (61%), BMD (41%), osteophytes (41%) and subchondral bone plate thickness (39%). Subchondral bone plate microstructure is not comprehensively, subarticular spongiosa microstructure is well characterized. The subarticular spongiosa is altered shortly before the subchondral bone plate. These early changes involve degradation of subarticular trabecular elements, reduction of their number, loss of bone volume and reduced mineralization. Soon thereafter, the previously normal subchondral bone plate becomes thicker. Its porosity first increases, then decreases. CONCLUSION: The specific human topographical pattern of a thinner subchondral bone plate in the region below both menisci is present solely in the larger species (partly in rabbits), but absent in rodents, an important fact to consider when designing animal studies examining subchondral consequences of meniscus damage. Large animal models are capable of providing high topographical detail, suggesting that they may represent suitable study systems reflecting the clinical complexities. For advanced OA, significant gaps of knowledge exist. Future investigations assessing the subchondral bone in a standardized fashion are warranted.

A Photopolymerizable Biocompatible Hyaluronic Acid Hydrogel Promotes Early Articular Cartilage Repair in a Minipig Model In Vivo.

Articular cartilage defects represent an unsolved clinical challenge. Photopolymerizable hydrogels are attractive candidates supporting repair. This study investigates the short-term safety and efficacy of two novel hyaluronic acid (HA)-triethylene glycol (TEG)-coumarin hydrogels photocrosslinked in situ in a clinically relevant large animal model. It is hypothesized that HA-hydrogel-augmented microfracture (MFX) is superior to MFX in enhancing early cartilage repair, and that the molar degree of substitution and concentration of HA affects repair. Chondral full-thickness defects in the knees of adult minipigs are treated with either 1) debridement (No MFX), 2) debridement and MFX, 3) debridement, MFX, and HA hydrogel (30% molar derivatization, 30 mg mL-1 HA; F3) (MFX+F3), and 4) debridement, MFX, and HA hydrogel (40% molar derivatization, 20 mg mL-1 HA; F4) (MFX+F4). After 8 weeks postoperatively, MFX+F3 significantly improves total macroscopic and histological scores compared with all other groups without negative effects, besides significantly enhancing the individual repair parameters "defect architecture," "repair tissue surface" (compared with No MFX, MFX), and "subchondral bone" (compared with MFX). These data indicate that photopolymerizable HA hydrogels enable a favorable metastable microenvironment promoting early chondrogenesis in vivo. This work also uncovers a mechanism for effective HA-augmented cartilage repair by combining lower molar derivatization with higher concentrations.

rAAV TGF-ß and FGF-2 Overexpression via pNaSS-Grafted PCL Films Stimulates the Reparative Activities of Human ACL Fibroblasts.

Lesions in the human anterior cruciate ligament (ACL) are frequent, unsolved clinical issues due to the limited self-healing ability of the ACL and lack of treatments supporting full, durable ACL repair. Gene therapy guided through the use of biomaterials may steadily activate the processes of repair in sites of ACL injury. The goal of the present study was to test the hypothesis that functionalized poly(sodium styrene sulfonate)-grafted poly(ε-caprolactone) (pNaSS-grafted PCL) films can effectively deliver recombinant adeno-associated virus (rAAV) vectors as a means of overexpressing two reparative factors (transforming growth factor beta-TGF-ß and basic fibroblast growth factor-FGF-2) in primary human ACL fibroblasts. Effective, durable rAAV reporter red fluorescent protein and candidate TGF-ß and FGF-2 gene overexpression was achieved in the cells for at least 21 days, especially when pNaSS-grafted PCL films were used versus control conditions, such as ungrafted films and systems lacking vectors or films (between 1.8- and 5.2-fold differences), showing interactive regulation of growth factor production. The expression of TGF-ß and FGF-2 from rAAV via PCL films safely enhanced extracellular matrix depositions of type-I/-III collagen, proteoglycans/decorin, and tenascin-C (between 1.4- and 4.5-fold differences) in the cells over time with increased levels of expression of the specific transcription factors Mohawk and scleraxis (between 1.7- and 3.7-fold differences) and without the activation of the inflammatory mediators IL-1ß and TNF-α, most particularly with pNaSS-grafted PCL films relative to the controls. This work shows the value of combining rAAV gene therapy with functionalized PCL films to enhance ACL repair.

Bio-responsive and multi-modality imaging nanomedicine for osteoarthritis theranostics.

Osteoarthritis (OA) is one of the most common joint diseases currently, characterized by the gradual degradation of cartilage, remodeling of subchondral bone, development of synovitis, degenerative alterations in the menisci, and formation of osteophytes. Generally, loss of articular cartilage is the most common pathological manifestation of OA. However, owing to the lack of blood vessels and nerves, the damaged cartilage is unable to execute self-repair. Therefore, early detection and treatment of cartilage lesions are extremely vital. Given that precise diagnosis and therapeutic strategy are indispensable from the basic pathological features of OA, an ideal therapeutic strategy should cater to the specific features of the OA microenvironment to achieve disease-modifying therapy. To date, nanomedicine presents an opportunity to achieve the precisely targeted delivery of agents and stimuli-sensitive release at the optimum dose, which may be coupled with a controlled release profile and reduced side effects. This review mainly summarizes inherent and microenvironment traits of OA and outlines stimuli-responsive nanotherapies, including internal bio-responsive (e.g., reactive oxygen species, pH, and protease) and external (e.g., photo stimuli, temperature, ultrasound, and magnetic field) responsive nanotherapies. Furthermore, multi-targeted therapeutic strategies combined with multi-modality imaging are also discussed. In general, future exploration of more novel stimuli-responsive nanotherapies that can be used for early diagnosis and cartilage targeting may help ameliorate OA-related cartilage damage, decrease pain, and promote joint function.

Cytotoxic effects of different mouthwash solutions on primary human articular chondrocytes and normal human articular cartilage - an in vitro study.

OBJECTIVES: To compare the cytotoxicity of octenidine dihydrochloride and chlorhexidine gluconate at different concentrations on primary human articular chondrocytes and cartilage. MATERIALS AND METHODS: Primary cultures of human normal adult articular chondrocytes were exposed to octenidine dihydrochloride (0.001562%, 0.003125%, 0.00625%, 0.0125%, 0.025%, 0.05%, and 0.1%), chlorhexidine gluconate (0.003125%, 0.00625%, 0.0125%, 0.025%, 0.05%, 0.1%, and 0.2%), and control (Dulbecco's modified Eagle medium or phosphate-buffered saline) for 30 s. Normal human articular cartilage explants were exposed to octenidine dihydrochloride (0.1% versus control) and chlorhexidine gluconate (0.1% versus control) for 30 s. The viability of human articular chondrocytes was measured by Trypan blue staining, Cell Proliferation Reagent WST-1, and Live/Dead staining. The proliferation of human chondrocytes was measured using the Cell Proliferation Reagent WST-1. The viability of human articular cartilage explants was measured by using Live/Dead staining. RESULTS: Octenidine dihydrochloride and chlorhexidine gluconate exposure decreased cell viability and proliferation in a dose-dependent manner in primary human articular chondrocytes. Octenidine dihydrochloride and chlorhexidine gluconate exposure decreased cell viability in human articular cartilage explant cultures. CONCLUSION: The degree of toxicity varied between octenidine dihydrochloride and chlorhexidine gluconate, with chlorhexidine gluconate being less toxic than octenidine dihydrochloride at the same concentration. Additionally, both octenidine dihydrochloride and chlorhexidine gluconate evaluation had cytotoxic effects on human articular cartilage. Therefore, dosing for the antimicrobial mouthwash ingredients administration would ideally be determined to remain below IC50. CLINICAL RELEVANCE: These data support the in vitro safety of antimicrobial mouthwashes on primary adult human articular chondrocytes.

Etiology, Classification, Diagnostics, and Conservative Management of Osteochondral Lesions of the Talus. 2023 Recommendations of the Working Group "Clinical Tissue Regeneration" of the German Society of Orthopedics and Traumatology.

METHODS: Peer-reviewed literature was analyzed regarding different topics relevant to osteochondral lesions of the talus (OLTs) treatment. This process concluded with a statement for each topic reflecting the best scientific evidence available for a particular diagnostic or therapeutic concept, including the grade of recommendation. Besides the scientific evidence, all group members rated the statements to identify possible gaps between literature and current clinical practice. CONCLUSION: In patients with minimal symptoms, OLT progression to ankle osteoarthritis is unlikely. Risk factors for progression are the depth of the lesion on MRI, subchondral cyst formation, and the extent of bone marrow edema. Conservative management is the adaptation of activities to the performance of the ankle joint. A follow-up imaging after 12 months helps not to miss any progression. It is impossible to estimate the probability of success of conservative management from initial symptoms and imaging. Cast immobilization is an option in OLTs in children, with a success rate of approximately 50%, although complete healing, estimated from imaging, is rare. In adults, improvement by conservative management ranges between 45% and 59%. Rest and restrictions for sports activities seem to be more successful than immobilization. Intra-articular injections of hyaluronic acid and platelet-rich plasma can improve pain and functional scores for more than 6 months. If 3 months of conservative management does not improve symptoms, surgery can be recommended.

Empfehlungen der AG Klinische Geweberegeneration zur Behandlung von Knorpelschäden am Kniegelenk. / Empfehlungen der AG Klinische Geweberegeneration zur Behandlung von Knorpelschäden am Kniegelenk.

The Working Group of the German Orthopedic and Trauma Society (DGOU) on Tissue Regeneration has published recommendations on the indication of different surgical approaches for treatment of full-thickness cartilage defects in the knee joint in 2004, 2013 and 2016. Based upon new scientific knowledge and new developments, this recommendation is an update based upon the best clinical evidence available. In addition to prospective randomised controlled clinical trials, this also includes studies with a lower level of evidence. In the absence of evidence, the decision is based on a consensus process within the members of the working group.The principle of making decision dependent on defect size has not been changed in the new recommendation either. The indication for arthroscopic microfracturing has been reduced up to a defect size of 2 cm2 maximum, while autologous chondrocyte implantation is the method of choice for larger cartilage defects. Additionally, matrix-augmented bone marrow stimulation (mBMS) has been included in the recommendation for defects ranging from 1 to 4.5 cm2. For the treatment of smaller osteochondral defects, in addition to osteochondral transplantation (OCT), mBMS is also recommended. For larger defects, matrix-augmented autologous chondrocyte implantation (mACI/mACT) in combination with augmentation of the subchondral bone is recommended.

Intra-articular injection of rAAV-hFGF-2 ameliorates monosodium iodoacetate-induced osteoarthritis in rats via inhibiting TLR-4 signaling and activating TIMP-1.

Osteoarthritis (OA) is a chronic debilitating degenerative disorder leading to structural, and functional anomaly of the joint. The present study tests the hypothesis that overexpression of the basic fibroblast growth factor (FGF-2) via direct rAAV-mediated gene transfer suppresses monosodium iodoacetate (MIA)-induced knee OA in rats relative to control (reporter rAAV-lacZ vector) gene transfer by intra-articular injection. Rats were treated with 20 µl rAAV-hFGF-2 on weekly basis; on days 7, 14, and 21 after single intra-articular injection of MIA (3 mg/50 µl saline). FGF-2 reduced knee joint swelling and improved motor performance and muscle coordination as evidenced by increased distance travelled, mean speed, rearing frequency in open field test (OFT) as well as fall-off latency in rotarod test together with reduced immobility time in OFT. Moreover, FGF-2 attenuated MIA-related radiological and histological alterations. Indeed, FGF-2 decreased knee joint inflammatory biomarker as demonstrated by reduced mRNA expression of toll like receptor (TLR)-4 and its downstream mediators such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and high motility group box (HMGB) 1. In parallel, FGF-2 attenuated knee joint degradation biomarkers as reflected by the downregulation of ADAMTS-5 mRNA expression and matrix metalloproteinase 13 (MMP-13) content together with the up-regulation of tissue inhibitor of metalloproteinase (TIMP)-1 mRNA expression. These findings suggest a potential therapeutic role for FGF-2 against MIA-induced knee OA in rats via inhibition of TLR4 signaling and activating TIMP-1, resulting in down-regulation of ADAMTS-5 and MMP-13.

The Association Between Quadriceps Strength and Synovitis in Knee Osteoarthritis: An Exploratory Study From the Osteoarthritis Initiative.

OBJECTIVE: The aim of this study was to explore the association between quadriceps strength and synovitis in knee osteoarthritis (KOA). METHODS: This study was derived from the Osteoarthritis Initiative (OAI), which recruited adults from the OAI cohort with or at risk of KOA. Knees with complete records of isometric quadriceps strength and effusion-synovitis and Hoffa-synovitis assessments were included. Quadriceps strength was measured isometrically at baseline. Effusion-synovitis and Hoffa-synovitis were measured using the Magnetic Resonance Imaging Osteoarthritis Knee Score at baseline and at 1-year and 2-year follow-ups. Generalized estimating equations were used to analyze the associations of baseline quadriceps strength with changes in effusion-synovitis and Hoffa-synovitis in multivariable analyses. Additionally, analyses were stratified by synovitis-driven inflammatory phenotypes. RESULTS: A total of 1513 knees were included in this study. In total, 61% of the subjects were female; subjects had an average age of 61.9 (SD 8.8) years and a mean BMI of 29.4 (SD 4.7). Regarding the whole population, baseline quadriceps strength was negatively associated with baseline effusion-synovitis and follow-up changes in effusion-synovitis (odds ratio [OR] 0.77-0.86), but no significant association was observed in terms of Hoffa-synovitis. Stratified by synovitis-driven inflammatory phenotype, baseline quadriceps strength was significantly associated with follow-up changes in effusion-synovitis-but not in Hoffa-synovitis-in the population with existing effusion-synovitis (OR 0.75-0.79). CONCLUSION: Higher baseline quadriceps strength was negatively associated with changes in effusion-synovitis-but not in Hoffa-synovitis-especially in the population with existing effusion-synovitis. Our findings suggested a potential protective role of the quadriceps in effusion-synovitis.

Advanced Gene Therapy Strategies for the Repair of ACL Injuries.

The anterior cruciate ligament (ACL), the principal ligament for stabilization of the knee, is highly predisposed to injury in the human population. As a result of its poor intrinsic healing capacities, surgical intervention is generally necessary to repair ACL lesions, yet the outcomes are never fully satisfactory in terms of long-lasting, complete, and safe repair. Gene therapy, based on the transfer of therapeutic genetic sequences via a gene vector, is a potent tool to durably and adeptly enhance the processes of ACL repair and has been reported for its workability in various experimental models relevant to ACL injuries in vitro, in situ, and in vivo. As critical hurdles to the effective and safe translation of gene therapy for clinical applications still remain, including physiological barriers and host immune responses, biomaterial-guided gene therapy inspired by drug delivery systems has been further developed to protect and improve the classical procedures of gene transfer in the future treatment of ACL injuries in patients, as critically presented here.