Repair Of Articular Cartilage Defects Research Articles

Magnetic Soft Catheter Robot System for Minimally Invasive Treatments of Articular Cartilage Defects.

Articular cartilage defects are among the most common orthopedic diseases, which seriously affect patients' health and daily activities, without prompt treatment. The repair biocarrier-based treatment has shown great promise. Total joint injection and open surgery are two main methods to deliver functional repair biocarriers into the knee joint. However, the exhibited drawbacks of these methods hinder their utility. The repair effect of total joint injection is unstable due to the low targeting rate of the repair biocarriers, whereas open surgery causes serious trauma to patients, thereby prolonging the postoperative healing time. In this study, we develop a magnetic soft catheter robot (MSCR) system to perform precise in situ repair of articular cartilage defects with minimal incision. The MSCR processes a size of millimeters, allowing it to enter the joint cavity through a tiny skin incision to reduce postoperative trauma. Meanwhile, a hybrid control strategy combining neural network and visual servo is applied to sequentially complete the coarse and fine positioning of the MSCR on the cartilage defect sites. After reaching the target, the photosensitive hydrogel is injected and anchored into the defect sites through the MSCR, ultimately completing the in situ cartilage repair. The in vitro and ex vivo experiments were conducted on a 3D printed human femur model and an isolated porcine femur, respectively, to demonstrate the potential of our system for the articular cartilage repair.

3D Printing of Maturable Tissue Constructs Using a Cell‐Adaptable Nanocolloidal Hydrogel

Abstract3D‐printed cell‐laden hydrogels as tissue constructs show great promise in generating living tissues for medicine. Currently, the maturation of 3D‐printed constructs into living tissues remains challenge, since commonly used hydrogels struggle to provide an ideal microenvironment for the seeded cells. In this study, a cell‐adaptable nanocolloidal hydrogel is created for 3D printing of maturable tissue constructs. The nanocolloidal hydrogel is composed of interconnected nanoparticles, which is prepared by the self‐assembly and subsequent photocrosslinking of the gelatin methacryloyl solutions. Cells can get enough space to grow and migrate within the hydrogel through squeezing the flexible nanocolloidal networks. Meanwhile, the nanostructure can promote the seeded cells to proliferate and produce matrix proteins through mechanotransduction. Using digital light process‐based 3D printing technology, it can rapidly customize cartilage tissue constructs. After implantation, these tissue constructs efficiently matured into cartilage tissues for the articular cartilage defect repair and ear cartilage reconstruction in vivo. The 3D printing of maturable tissue constructs using the nanocolloidal hydrogel shows potential for future clinical applications.

Fabrication of an injectable hydrogel scaffold embedding kartogenin-encapsulated PLGA microsphere with long-term drug release to promote chondrogenesis

To address the long-lasting challenges on repair of articular cartilage defects in clinic, cartilage tissue engineering (CTE) strategy aims to develop favorable scaffolds to undertake mechanical support and simulate the cellular microenvironment for remodeling or replacing the defective cartilage tissues. Wherein, facile operation, favorable mechanical strength, excellent biocompatibility, suitable biodegradability, and innate chondrogenic ability are crucially adjective in CTE. Herein, we fabricated an injectable tetra-PEG hydrogel scaffold embedding kartogenin-encapsulated poly (lactic-co-glycolic acid) (PLGA@KGN) microspheres by means of the premix membrane emulsification (PME) method and quick sol-gel transformation. The unform tetra-PEG network endowed this composite hydrogel (tetra-PEG/PLGA@KGN) with favorable pores, easy injectability, mechanical strength and lower swelling ratio, while the internal small KGN drugs with the unique differentiation ability into chondrocytes could be slowly released for a long period of time, thus capably allowing the maintenance of the drug's effective concentration and long-lasting sustained release up to >28 days and persistently enhancing its chondrogenic efficiency. In vitro results indicated its satisfactory compatibility for supporting the cell activity, proliferation, and differentiation. Overall, due to improved mechanical property and sustainable KGN release behavior, this designable hydrogel scaffold may provide an option with clinical translational potential for cartilage repair.

Combination of a human articular cartilage-derived extracellular matrix scaffold and microfracture techniques for cartilage regeneration: A proof of concept in a sheep model

BackgroundThe utilization of decellularized extracellular matrix has gained considerable attention across numerous areas in regenerative research. Of particular interest is the human articular cartilage-derived extracellular matrix (hACECM), which presents as a promising facilitator for cartilage regeneration. Concurrently, the microfracture (MF) ​technique, a well-established marrow stimulation method, has proven efficacious in the repair of cartilage defects. However, as of the current literature review, no investigations have explored the potential of a combined application of hACECM and the microfracture technique in the repair of cartilage defects within a sheep model. HypothesisThe combination of hACECM scaffold and microfracture will result in improved repair of full-thickness femoral condyle articular cartilage defects compared to the use of either technique alone. Study designControlled laboratory study. MethodsFull-thickness femoral condyle articular cartilage defect (diameter, 7.0 ​mm; debrided down to the subchondral bone plate) were created in the weight-bearing area of the femoral medial and lateral condyles (n ​= ​24). All of defected sheep were randomly divided into four groups: control, microfracture, hACECM scaffold, and hACECM scaffold ​+ ​microfracture. After 3, 6 and 12 months, the chondral repair was assessed for standardized (semi-) quantitative macroscopic, imaging, histological, immunohistochemical, mechanics, and biochemical analyses in each group. ResultAt 3, 6 and 12 months after implantation, the gross view and pathological staining of regenerative tissues were better in the hACECM scaffold and hACECM scaffold ​+ ​microfracture groups than in the microfracture and control groups; Micro-CT result showed that the parameters about the calcified layer of cartilage and subchondral bone were better in the hACECM scaffold and hACECM scaffold ​+ ​microfracture groups than the others, and excessive subchondral bone proliferation in the microfracture group. The results demonstrate that human cartilage extracellular matrix scaffold alone is an efficient, safe and simple way to repair cartilage defects. ConclusionhACECM scaffolds combined with/without microfracture facilitate chondral defect repair. The translational potential of this articlePreclinical large animal models represent an important adjunct and surrogate for studies on articular cartilage repair, while the sheep stifle joint reflects many key features of the human knee and are therefore optimal experimental model for future clinical application in human. In this study, we developed a human articular cartilage-derived extracellular matrix scaffold and to verify the viability of its use in sheep animal models. Clinical studies are warranted to further quantify the effects of hACECM scaffolds in similar settings.

An injectable and 3D printable pro-chondrogenic hyaluronic acid and collagen type II composite hydrogel for the repair of articular cartilage defects

Current treatments for repairing articular cartilage defects are limited. However, pro-chondrogenic hydrogels formulated using articular cartilage matrix components (such as hyaluronic acid (HA) and collagen type II (Col II)), offer a potential solution if they could be injected into the defect via minimally invasive arthroscopic procedures, or used as bioinks to 3D print patient-specific customised regenerative scaffolds—potentially combined with cells. However, HA and Col II are difficult to incorporate into injectable/3D printable hydrogels due to poor physicochemical properties. This study aimed to overcome this by developing an articular cartilage matrix-inspired pro-chondrogenic hydrogel with improved physicochemical properties for both injectable and 3D printing (3DP) applications. To achieve this, HA was methacrylated to improve mechanical properties and mixed in a 1:1 ratio with Col I, a Col I/Col II blend or Col II. Col I possesses superior mechanical properties to Col II and so was hypothesised to enhance hydrogel mechanical properties. Rheological analysis showed that the pre-gels had viscoelastic and shear thinning properties. Subsequent physicochemical analysis of the crosslinked hydrogels showed that Col II inclusion resulted in a more swollen and softer polymer network, without affecting degradation time. While all hydrogels exhibited exemplary injectability, only the Col I-containing hydrogels had sufficient mechanical stability for 3DP applications. To facilitate 3DP of multi-layered scaffolds using methacrylated HA (MeHA)-Col I and MeHA-Col I/Col II, additional mechanical support in the form of a gelatin slurry support bath freeform reversible embedding of suspended hydrogels was utilised. Biological analysis revealed that Col II inclusion enhanced hydrogel-embedded MSC chondrogenesis, thus MeHA-Col II was selected as the optimal injectable hydrogel, and MeHA-Col I/Col II as the preferred bioink. In summary, this study demonstrates how tailoring biomaterial composition and physicochemical properties enables development of pro-chondrogenic hydrogels with potential for minimally invasive delivery to injured articular joints or 3DP of customised regenerative implants for cartilage repair.

Repair of full-thickness articular cartilage defects with a 3DP-anchored three-phase complex

IntroductionTo repair cartilage defect as well as the calcified cartilage layer (CCL) and bone tissue, there is need to fabricate a three-phase complex that mimics the natural cartilage tissue. Materials and methodsSF/Col-Ⅱ/HA scaffolds were constructed by low-temperature 3D printing, and to prepare a three-phase complex. The microstructure were showed using a SEM image analysis program. To observe collagen and glycosaminoglycan expression and analyze morphometric parameters, HE staining was performed to reveal new cartilage. Immunohistochemical were performed to investigate the collagen content and defect repair status in the new cartilage group in vitro and vivo. ResultsPhysical and biochemical properties and biocompatibility of three-phase complex met the requirements of constructing tissue-engineered cartilage. The OD values increased gradually at different time points. With increasing culture time, the OD values showed an upward trend. The HE and immunohistochemical staining results showed that new cartilage had formed at the defect and new cartilage formation occurred during in vivo repair. Conclusion3DP-anchored three-phase complexes have good physical and biochemical properties and biocompatibility and thus represent an alternative cartilage tissue engineering material.

Decellularized allogeneic cartilage paste with human costal cartilage and crosslinked hyaluronic acid-carboxymethyl cellulose carrier augments microfracture for improved articular cartilage repair

Articular cartilage lacks natural healing abilities and necessitates surgical treatments for injuries. While microfracture (MF) is a primary surgical approach, it often results in the formation of unstable fibrocartilage. Delivering hyaline cartilage directly to defects poses challenges due to the limited availability of autologous cartilage and difficulties associated with allogeneic cartilage delivery. We developed a decellularized allogeneic cartilage paste (DACP) using human costal cartilage mixed with a crosslinked hyaluronic acid (HA)-carboxymethyl cellulose (CMC) carrier. The decellularized allogeneic cartilage preserved the extracellular matrix and the nanostructure of native hyaline cartilage. The crosslinked HA-CMC carrier provided shape retention and moldability. In vitro studies confirmed that DACP did not cause cytotoxicity and promoted migration, proliferation, and chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells. After 6 months of implantation in rabbit knee osteochondral defects, DACP combined with MF outperformed MF alone, demonstrating improved gait performance, defect filling, morphology, extracellular matrix deposition, and biomechanical properties similar to native cartilage. Thus, DACP offers a safe and effective method for articular cartilage repair, representing a promising augmentation to MF. Statement of significanceDirectly delivering hyaline cartilage to repair articular cartilage defects is an ideal treatment. However, current allogeneic cartilage products face delivery challenges. In this study, we developed a decellularized allogeneic cartilage paste (DACP) by mixing human costal cartilage with crosslinked hyaluronic acid (HA)-carboxymethyl cellulose (CMC). DACP preserves extracellular matrix components and nanostructures similar to native cartilage, with HA-CMC ensuring shape retention and moldability. Our study demonstrates improved cartilage repair by combining DACP with microfracture, compared to microfracture alone, in rabbit knee defects over 6 months. This is the first report showing better articular cartilage repair using decellularized allogeneic cartilage with microfracture, without the need for exogenous cells or bioactive substances.

Review of Caplan (1991) on cell-based therapeutic technology using Mesenchymal Stem Cells

This classic discusses the original 1991 publication ‘Mesenchymal Stem Cells (MSCs)’ by Dr. Caplan on the emergence of a new therapeutic technology of self-cell repair using MSCs. After the original classic publication, a large number of methods to regenerate injured tissue have been reported. Currently, MSCs are used clinically to repair articular cartilage defects, liver cirrhosis, cerebral infarction, spinal cord injury, graft-versus-host disease and others. As a result, MSCs are considered one of the most important cell sources for regenerative medicine. An MSC has been demonstrated to be a multipotent stem cell in cell culture and was thought to contribute to the regeneration of injured tissue at transplant sites, but recently, the concept of MSCs has changed such that they are now referred to as "medicinal signaling cells," owing to their often indirect effects on tissue repair and regeneration. Regardless of the name, either mesenchymal stem cells or medicinal signaling cells, MSCs will be used to regenerate injured tissue more widely in the near future.

Autologous Mesenchymal Stromal Cells Immobilized in Plasma-Based Hydrogel for the Repair of Articular Cartilage Defects in a Large Animal Model.

The treatment of cartilage defects in trauma injuries and degenerative diseases represents a challenge for orthopedists. Advanced mesenchymal stromal cell (MSC)-based therapies are currently of interest for the repair of damaged cartilage. However, an approved system for MSC delivery and maintenance in the defect is still missing. This study aimed to evaluate the effect of autologous porcine bone marrow MSCs anchored in a commercially available polyglycolic acid-hyaluronan scaffold (Chondrotissue®) using autologous blood plasma-based hydrogel in the repair of osteochondral defects in a large animal model. The osteochondral defects were induced in twenty-four minipigs with terminated skeletal growth. Eight animals were left untreated, eight were treated with Chondrotissue® and eight received Chondrotissue® loaded with MSCs. The animals were terminated 90 days after surgery. Macroscopically, the untreated defects were filled with newly formed tissue to a greater extent than in the other groups. The histological evaluations showed that the defects treated with Chondrotissue® and Chondrotissue® loaded with pBMSCs contained a higher amount of hyaline cartilage and a lower amount of connective tissue, while untreated defects contained a higher amount of connective tissue and a lower amount of hyaline cartilage. In addition, undifferentiated connective tissue was observed at the edges of defects receiving Chondrotissue® loaded with MSCs, which may indicate the extracellular matrix production by transplanted MSCs. The immunological analysis of the blood samples revealed no immune response activation by MSCs application. This study demonstrated the successful and safe immobilization of MSCs in commercially available scaffolds and defect sites for cartilage defect repair.

Effect of storage media on chondrocyte viability during cold storage of osteochondral dowels.

Osteochondral allograft transplantation is a successfully proven method to repair articular cartilage defects and prevent the degenerative effects of osteoarthritis. The number of osteochondral transplantations that can be performed each year is limited by availability of donor cartilage tissue and storage time constraints. Osteochondral transplantation success has been linked to high chondrocyte viability of the donor cartilage tissue at the time of implantation. Determining optimal storage conditions for donor cartilage is essential for tissue banks to safely provide quality cartilage tissue. In this study, we compared three tissue/cell media (DMEM/F12, RPMI-1640 and X-VIVO 10) for their ability to maintain chondrocyte viability during hypothermic storage for 28days. Porcine osteochondral dowels were stored in each media for 28days and cell viability was assessed every 7days. Over the 28day storage period, the chondrocyte viability of dowels stored in DMEM/F12, RPMI-1640, and X-VIVO 10 media all declined in a similar fashion. Our results show that all three media were equivalent in their ability to maintain cell viability of the cartilage tissue and provides rationale for the use of lower cost cell media (DMEM/F12 and RPMI-1640) for hypothermic storage of articular cartilage tissue.

Construction of 3D-Bioprinted cartilage-mimicking substitute based on photo-crosslinkable Wharton's jelly bioinks for full-thickness articular cartilage defect repair.

Three-dimensional (3D) bioprinted cartilage-mimicking substitutes for full-thickness articular cartilage defect repair have emerged as alternatives to in situ defect repair models. However, there has been very limited breakthrough in cartilage regeneration based on 3D bioprinting owing to the lack of ideal bioinks with printability, biocompatibility, bioactivity, and suitable physicochemical properties. In contrast to animal-derived natural polymers or acellular matrices, human-derived Wharton's jelly is biocompatible and hypoimmunogenic with an abundant source. Although acellular Wharton's jelly can mimic the chondrogenic microenvironment, it remains challenging to prepare both printable and biologically active bioinks from this material. Here, we firstly prepared methacryloyl-modified acellular Wharton's jelly (AWJMA) using a previously established photo-crosslinking strategy. Subsequently, we combined methacryloyl-modified gelatin with AWJMA to obtain a hybrid hydrogel that exhibited both physicochemical properties and biological activities that were suitable for 3D bioprinting. Moreover, bone marrow mesenchymal stem cell-loaded 3D-bioprinted cartilage-mimicking substitutes had superior advantages for the survival, proliferation, spreading, and chondrogenic differentiation of bone marrow mesenchymal stem cells, which enabled satisfactory repair of a model of full-thickness articular cartilage defect in the rabbit knee joint. The current study provides a novel strategy based on 3D bioprinting of cartilage-mimicking substitutes for full-thickness articular cartilage defect repair.

In major joint diseases the human synovium retains its potential to form repair cartilage

The inner surface layer of human joints, the synovium, is a source of stem cells for the repair of articular cartilage defects. We investigated the potential of the normal human synovium to form novel cartilage and compared its chondrogenic capacity with that of two patient groups suffering from major joint diseases: young adults with femoro-acetabular impingement syndromes of the hip (FAI), and elderly individuals with osteoarthritic degeneration of the knee (OA). Synovial membrane explants of these three patient groups were induced in vitro to undergo chondrogenesis by growth factors: bone morphogenetic protein-2 (BMP-2) alone, transforming growth factor-β1 (TGF-β1) alone, or a combination of these two. Quantitative evaluations of the newly formed cartilages were performed respecting their gene activities, as well as the histochemical, immunhistochemical, morphological and histomorphometrical characteristics. Formation of adult articular-like cartilage was induced by the BMP-2/TGF-β1 combination within all three groups, and was confirmed by adequate gene-expression levels of the anabolic chondrogenic markers; the levels of the catabolic markers remained low. Our data reveal that the chondrogenic potential of the normal human synovium remains uncompromised, both in FAI and OA. The potential of synovium-based clinical repair of joint cartilage may thus not be impaired by age-related joint pathologies.

Clinical Trials with Mesenchymal Stem Cell Therapies for Osteoarthritis: Challenges in the Regeneration of Articular Cartilage.

Osteoarthritis (OA) is a whole-joint disease primarily characterized by the deterioration of hyaline cartilage. Current treatments include microfracture and chondrocyte implantation as early surgical strategies that can be combined with scaffolds to repair osteochondral lesions; however, intra-articular (IA) injections or implantations of mesenchymal stem cells (MSCs) are new approaches that have presented encouraging therapeutic results in animal models and humans. We critically reviewed clinical trials with MSC therapies for OA, focusing on their effectiveness, quality, and outcomes in the regeneration of articular cartilage. Several sources of autologous or allogeneic MSCs were used in the clinical trials. Minor adverse events were generally reported, indicating that IA applications of MSCs are potentially safe. The evaluation of articular cartilage regeneration in human clinical trials is challenging, particularly in the inflammatory environment of osteoarthritic joints. Our findings indicate that IA injections of MSCs are efficacious in the treatment of OA and the regeneration of cartilage, but that they may be insufficient for the full repair of articular cartilage defects. The possible interference of clinical and quality variables in the outcomes suggests that robust clinical trials are still necessary for generating reliable evidence with which to support these treatments. We suggest that the administration of just-sufficient doses of viable cells in appropriate regimens is critical to achieve effective and durable effects. In terms of future perspectives, genetic modification, complex products with extracellular vesicles derived from MSCs, cell encapsulation in hydrogels, and 3D bioprinted tissue engineering are promising approaches with which to improve MSC therapies for OA.

Glycopolypeptide hydrogels with adjustable enzyme-triggered degradation: A novel proteoglycans analogue to repair articular-cartilage defects.

Proteoglycans (PGs), also known as a viscous lubricant, is the main component of the cartilage extracellular matrix (ECM). The loss of PGs is accompanied by the chronic degeneration of cartilage tissue, which is an irreversible degeneration process that eventually develops into osteoarthritis (OA). Unfortunately, there is still no substitute for PGs in clinical treatments. Herein, we propose a new PGs analogue. The Glycopolypeptide hydrogels in the experimental groups with different concentrations were prepared by Schiff base reaction (Gel-1, Gel-2, Gel-3, Gel-4, Gel-5 and Gel-6). They have good biocompatibility and adjustable enzyme-triggered degradability. The hydrogels have a loose and porous structure suitable for the proliferation, adhesion, and migration of chondrocytes, good anti-swelling, and reduce the reactive oxygen species (ROS) in chondrocytes. In vitro experiments confirmed that the glycopolypeptide hydrogels significantly promoted ECM deposition and up-regulated the expression of cartilage-specific genes, such as type-II collagen, aggrecan, and glycosaminoglycans (sGAG). In vivo, the New Zealand rabbit knee articular cartilage defect model was established and the hydrogels were implanted to repair it, the results showed good cartilage regeneration potential. It is worth noting that the Gel-3 group, with a pore size of 122​±​12​μm, was particularly prominent in the above experiments, and provides a theoretical reference for the design of cartilage-tissue regeneration materials in the future.

Effect study of exosomes derived from platelet-rich plasma in the treatment of knee cartilage defects in rats

BackgroundThe repair of articular cartilage defects has always been a difficult problem. We aimed to investigate the therapeutic effect of intra-articular injection of platelet-rich plasma (RPR) and PRP-derived exosomes (PRP-Exos) on cartilage defects in rat knee joints and then provide experience for the use of PRP-exos in cartilage defect repair.MethodsRat abdominal aortic blood was collected, and PRP was extracted by two-step centrifugation. PRP-exos were obtained by kit extraction, and PRP-exos were identified by various methods. After the rats were anesthetized, a cartilage defect subchondral bone was created at the proximal end of the origin of the femoral cruciate ligament with a drill. SD rats were divided into 4 groups, including PRP group, 50 μg/ml PRP-exos group, 5 μg/ml PRP-exos group, and control group. One week after the operation, 50 μg/ml PRP, 50 μg/ml PRP-exos, 5 μg/ml PRP-exos and normal saline were injected into the knee joint cavity of rats in each group, once a week. A total of two injections were given. On the 5th and 10th week after drug injection, the serum levels of matrix metalloproteinase 3 (MMP-3) and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) were detected by each treatment method, respectively. The rats were killed at the 5th and 10th weeks, respectively, and the cartilage defect repair was observed and scored. The defect repair tissue sections were used for HE staining and type II collagen immunohistochemical staining.ResultsThe histological results showed that both PRP-exos and PRP could promote cartilage defect repair and type II collagen formation, and the promoting effect of PRP-exos was significantly better than that of PRP. In addition, enzyme-linked immunosorbent assay (ELISA) results showed that compared with PRP, PRP-exos could significantly increase serum TIMP-1 and decrease serum MMP-3 in rats. And the promoting effect of PRP-exos was concentration dependent.ConclusionIntra-articular injection of PRP-exos and PRP can promote the repair of articular cartilage defects, and the therapeutic effect of PRP-exos is better than the same concentration of PRP. PRP-exos are expected to be an effective treatment for cartilage repair and regeneration.

Hierarchical porous ECM scaffolds incorporating GDF-5 fabricated by cryogenic 3D printing to promote articular cartilage regeneration

BackgroundIn recent years, there has been significant research progress on in situ articular cartilage (AC) tissue engineering with endogenous stem cells, which uses biological materials or bioactive factors to improve the regeneration microenvironment and recruit more endogenous stem cells from the joint cavity to the defect area to promote cartilage regeneration.MethodIn this study, we used ECM alone as a bioink in low-temperature deposition manufacturing (LDM) 3D printing and then successfully fabricated a hierarchical porous ECM scaffold incorporating GDF-5.ResultsComparative in vitro experiments showed that the 7% ECM scaffolds had the best biocompatibility. After the addition of GDF-5 protein, the ECM scaffolds significantly improved bone marrow mesenchymal stem cell (BMSC) migration and chondrogenic differentiation. Most importantly, the in vivo results showed that the ECM/GDF-5 scaffold significantly enhanced in situ cartilage repair.ConclusionIn conclusion, this study reports the construction of a new scaffold based on the concept of in situ regeneration, and we believe that our findings will provide a new treatment strategy for AC defect repair.

A versatile 3D-printable hydrogel for antichondrosarcoma, antibacterial, and tissue repair

• A novel hydrogel with biological activity and photothermal effect was synthesized. • The hydrogel can exert anti-tumor and antibacterial effect through photothermal effect. • The hydrogel can effectively promote the repair of articular cartilage defects in vivo . Following operative treatment of chondrosarcoma, post-surgery tissue reconstruction may be confronted with daunting challenges, including the delayed self-repair of defective tissue, tumor recurrence, and bacterial infection. To overcome these challenges, a methacrylic anhydride (MA) modified sericin (SerMA) solution mixed with procyanidins (PC) loaded polydopamine (PDA) modified ZIF-8 (PC@ZIF-8@PDA) nanoparticles to form a multifunctional PC@ZIF-8@PDA/SerMA hydrogel after exposure under blue light. Hydrogel products with pre-designed shapes were printed out by using the SerMA solution carrying PC@ZIF-8@PDA nanoparticles and chondrocytes, indicating that PC@ZIF-8@PDA/SerMA hydrogels with personalized shapes can be fabricated via 3D printing. Photocrosslinked PC@ZIF-8@PDA/SerMA hydrogel is able to kill chondrosarcoma cells and bacteria, like Staphylococcus aureus (S. aureus) , and Escherichia coli (E. coli) , by its photothermal activity combined with near-infrared radiation (NIR). The PC@ZIF-8@PDA/SerMA hydrogel exhibited an antioxidative activity and a good biocompatibility and was easily monitored by its florescent and photoacoustic properties. Rabbit articular cartilage defects were efficiently repaired by PC@ZIF-8@PDA/SerMA hydrogels with encapsulated corresponding autologous chondrocytes, and mice skin burning wounds were swiftly regenerated by applying this hydrogel. Hence, the PC@ZIF-8@PDA/SerMA hydrogel can be potentially applied to the clinic treatment of chondrosarcoma and tissue defect repair after chondrosarcoma resection due to its multifunction in the future.

4D Printed Shape Memory Polyurethane-Based Composite for Bionic Cartilage Scaffolds

Repair of articular cartilage defects is a major challenge in orthopedic surgery due to the deficient self-regeneration capability. Cartilage tissue engineering scaffolds provide a promising approach to cartilage defect repair. Proper mechanical properties, interconnected internal structure, customized shape, and minimally invasive treatment are urgent requirements for a qualified cartilage scaffold. Here, a shape memory composite used for cartilage defects is prepared by adding nanohydroxyapatite into a shape memory polyurethane matrix, exhibiting good mechanical properties and biocompatibility. Based on its rheological properties, the composite melt can be printed into 4D printed structures with high precision and quality in a simple and clean way. Inspired by the structure of mangroves, a bionic 4D printed cartilage scaffold is designed and manufactured, presenting a good shape memory performance at a temperature close to body temperature. The 4D printed cartilage scaffold can expand from a conveniently insertional shape to a deployed shape to match defect, providing a novel idea for the personalized and minimally invasive treatment of cartilage defects.

In situ fabrication of an anisotropic double-layer hydrogel as a bio-scaffold for repairing articular cartilage and subchondral bone injuries.

Articular cartilage is a smooth and elastic connective tissue playing load-bearing and lubricating roles in the human body. Normal articular cartilage comprises no blood vessels, lymphatic vessels, nerves, or undifferentiated cells, so damage self-repair is very unlikely. The injuries of articular cartilage are often accompanied by damage to the subchondral bone. The subchondral bone mainly provides mechanical support for the joint, and the successful repair of articular cartilage depends on the ability of the subchondral bone to provide a suitable environment. Currently, conventional repair treatments for articular cartilage and subchondral bone defects can hardly achieve good results due to the poor self-repairing ability of the cartilage Here, we propose a bioactive injectable double-layer hydrogel to repair articular cartilage and subchondral bone. The hydrogel scaffold mimics the multilayer structure of articular cartilage and subchondral bone. Agarose was used as a common base material for the double-layer hydrogel scaffold, in which a sodium alginate (SA)/agarose layer was used for the repair of artificially produced subchondral bone defects, while a decellularized extracellular matrix (dECM)/agarose layer was used for the repair of articular cartilage defects. The double-layer hydrogel scaffold is injectable, easy to use, and can fill in the damaged area. The hydrogel scaffold is also anisotropic both chemically and structurally. Animal experiments showed that the surface of the new cartilage tissue in the double-layer hydrogel scaffold group was closest to normal articular cartilage, with a structure similar to that of hyaline cartilage and a preliminary calcified layer. Moreover, the new subchondral bone in this group exhibited many regular bone trabeculae, and the new cartilage and subchondral bone were mechanically bound without mutual intrusion and tightly integrated with the surrounding tissue. The continuous double-layer hydrogel scaffold prepared in this study mimics the multilayer structure of articular cartilage and subchondral bone and promotes the functional repair of articular cartilage and subchondral bone, favoring close integration between the newborn tissue and the original tissue.

Ultrasound-triggered in situ gelation with ROS-controlled drug release for cartilage repair.

Cartilage defects are usually caused by acute trauma and chronic degeneration. However, it is still a great challenge to improve the repair of articular cartilage defects due to the limited self-regeneration capacity of such defects. Herein, a novel ROS-responsive in situ nanocomposite hydrogel loaded with kartogenin (KGN) and bone marrow-derived stem cells (BMSCs) was designed and constructed via the enzymatic reaction of fibrinogen and thrombin. Meanwhile, a ROS-responsive thioketal (TK)-based liposome was synthesized to load the chondrogenesis-inducing factor KGN, the bioenzyme thrombin and an ultrasound-sensitive agent PpIX. Under ultrasound stimulation, the TK-based liposome was destroyed, followed by in situ gelation of fibrinogen and thrombin. Moreover, sustained release of KGN was realized by regulating the ultrasound conditions. Importantly, ROS generation and KGN release within the microenvironment of the in situ fibrin hydrogel significantly promoted chondrogenic differentiation of BMSCs via the Smad5/mTOR signalling pathway and effectively improved cartilage regeneration in a rat articular cartilage defect model. Overall, the novel in situ nanocomposite hydrogel with ROS-controlled drug release has great potential for efficient cartilage repair.