Superlarge living hyaline cartilage graft contributed by the scale-changed porous 3D culture system for joint defect repair.

It is known that an excellent hyaline cartilage phenotype, an internal microstructure with safe crosslinking and available size flexibility are the key factors of cartilage grafts that allow for clinical application. Living hyaline cartilage grafts (LhCGs) constructed by phase-transfer hydrogel (PTCC) systems were reported to have a hyaline phenotype and bionic microstructure. By employing chondrocytes to secrete matrix in the hydrogel and then removing the material to obtain material-free tissuein vitro, LhCG technology exhibited superior performance in cartilage repair. However, PTCC systems could only produce small-sized LhCGs because of medium delivery limitations, which hinders the clinical application of LhCGs. In this study, we prepared three different noncrosslinked gelatin microspheres with diameters from 200 µm to 500 µm, which replaced the original pore-forming agent. The new PTCC system with the mixed and gradient porous structure was used for the preparation of superlarge LhCGs with a continuous structure and hyaline phenotype. Compared to the original technique, the porous gradient structure promoted nutrient delivery and cartilage matrix secretion. The small size of the microporous structure promoted the rapid formation of matrix junctions. The experimental group with a mixed gradient increased cartilage matrix secretion significantly by more than 50% compared to the that of the control. The LhCG final area reached 7 cm2without obvious matrix stratification in the mixed gradient group. The design of the scale-changed porous PTCC system will make LhCGs more promising for clinical application.

Stabilized albumin coatings on engineered xenografts for attenuation of acute immune and inflammatory responses.

Xenogeneic grafts are promising candidates for transplantation therapy due to their easily accessible sources. Nevertheless, the immune and inflammatory responses induced by xenografts need to be addressed for clinical use. A novel and facile method was introduced for the attenuation of immune and inflammatory responses by extending the immune evasion potential of albumin to the tissue engineering field and coating albumin, which could passivate biomaterial surfaces, onto xenografts. Albumin was first modified by dopamine to enhance its adhesion on graft surfaces. Porcine chondrocytes derived living hyaline cartilage graft (LhCG) and decellularized LhCG (dLhCG) were applied as xenograft models implanted in the omentum of rats. Both LhCG which contained porcine chondrocytes as well as secreted ECM and dLhCG which was mainly composed of the porcine source ECM showed alleviated immune and inflammatory responses after being coated with albumin at cell, protein and gene levels, respectively. Significantly less inflammatory cells including neutrophils, macrophages and lymphocytes were recruited according to pathological analysis and immunohistochemistry staining with lower gene expression encoding inflammation-related cytokines including MCP-1, IL-6 and IL-1ß after employing LhCG and dLhCG with albumin passivation coating.

Full-Scale Osteochondral Regeneration by Sole Graft of Tissue-Engineered Hyaline Cartilage without Co-Engraftment of Subchondral Bone Substitute.

In this study, full-scale osteochondral defects are hypothesized, which penetrate the articular cartilage layer and invade into subchondral bones, and can be fixed by sole graft of tissue-engineered hyaline cartilage without co-engraftment of any subchondral bone substitute. It is hypothesized that given a finely regenerated articular cartilage shielding on top, the restoration of subchondral bones can be fulfilled via spontaneous self-remodeling in situ. Hence, the key challenge of osteochondral regeneration lies in restoration of the non-self-regenerative articular cartilage. Here, traumatic osteochondral lesions to be repaired in rabbit knee models are endeavored using novel tissue-engineered hyaline-like cartilage grafts that are produced by 3D cultured porcine chondrocytes in vitro. Comparative trials are conducted in animal models that are implanted with living hyaline cartilage grafts (LhCG) and decellularized LhCG (dLhCG). Sound osteochondral regeneration is gradually revealed from both LhCG and dLhCG-implanted samples 50-100 d after implantation. Quality regeneration in both zones of articular cartilage and subchondral bones are validated by the restored osteochondral composition, structure, phenotype, and mechanical property, which validate the hypothesis of this study.

A novel autologous-made matrix using hyaline cartilage chips and platelet-rich growth factors for the treatment of full-thickness cartilage or osteochondral defects: Preliminary results.

PURPOSE: To report the clinical, functional, and magnetic resonance imaging (MRI)-based outcomes of a novel autologous-made matrix consisting of hyaline cartilage chips combined with mixed plasma poor rich in platelets clot and plasma rich in growth factors (PRGF) for the treatment of knee full-thickness cartilage or osteochondral defects. METHODS: Between July 2015 and January 2018, all patients with full-thickness cartilage or osteochondral defects undergoing this novel cartilage restoration surgical technique were approached for eligibility. Indications for this procedure included traumatic or atraumatic full-thickness knee cartilage defects or osteochondritis dissecans. Patients were included if they had no concomitant use of stem cells, previous ipsilateral cartilage repair procedure, or follow-up was less than 10 months. The outcomes included data on current symptoms, physical exam, patient-reported, and functional outcomes (visual analogue scale (VAS) for pain, Lysholm score, Tegner activity scale, International Knee Documentation Committee (IKDC) subjective form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, Lequesne index, and short form-12 (SF-12)) and the magnetic resonance observation of cartilage repair tissue (MOCART) score. These outcomes were compared to preoperative values, except for the MOCART score. RESULTS: Fifteen patients were included in this preliminary study: mean (standard deviation (SD), range) follow-up 15.9 months (7.2, 10-32), age 26.8 years (12.1, 16-58), and body mass index 23.2 (2.1, 19.3-26.9). There were 14 men (93%) and 1 woman (7%). There was a statistically significant improvement between pre- and postoperative periods for VAS for pain (p = 0.003), Lysholm score (p = 0.002), IKDC subjective form (p = 0.003), WOMAC for pain (p = 0.005), WOMAC for stiffness (p = 0.01), WOMAC for function (p = 0.002), Lequesne Index (p = 0.002), and SF-12 physical component summary (p = 0.007). The postoperative mean (SD; range) MOCART score was 70 (12.4; 40-85). CONCLUSIONS: The use of this novel cartilage restoration surgical technique provides excellent clinical, functional, and MRI-based outcomes in young, active individuals with full-thickness cartilage or osteochondral defects. LEVEL OF EVIDENCE: Level IV-Therapeutic case series.

Correction of Nasal Pinching.

The pinched nasal tip deformity often results as sequelae of prior nasal surgery. Conventional tip surgery techniques that overemphasize tip narrowing often deform the lateral crura and weaken support for the alar margin. The pinched nasal tip is characterized by the demarcation between the nasal tip and the alar lobule, isolating the tip from the surrounding nasal subunits. Lateral crural strut grafts with or without repositioning offer the surgeon a powerful maneuver that can help correct this functional and aesthetic deformity and restore a natural appearance to the nasal tip.

Return to Sport and Sports-Specific Outcomes After Osteochondral Allograft Transplantation in the Knee: A Systematic Review of Studies With at Least 2 Years' Mean Follow-Up.

PURPOSE: To report current data on return-to-sport rates and sports-specific patient-reported outcomes after osteochondral allograft (OCA) transplantation for cartilage defects of the knee. METHODS: We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines that included studies from 1975 to 2018 with a minimum 2-year mean follow-up that reported return-to-sport rates or sports-specific patient-reported outcomes. Outcomes, reoperations, and complications were provided in table format, and a subjective analysis was performed. RESULTS: This review included 13 studies with 772 patients who underwent OCA transplantation at a mean of 24 to 91 months' follow-up. The return-to-sport rate ranged from 75% to 82%. For patient-reported outcomes, the Knee Injury and Osteoarthritis Score Sport increased in 4 studies, the Tegner activity scale score increased in 3 studies but decreased in 1, and the Marx activity scale score increased in 1 study but decreased in 2. Studies reporting improvements in the Cincinnati Knee Score and Knee Injury and Osteoarthritis Score Sport reached the minimal clinically important difference. The reoperation rate was high (ranging from 34% to 53% in more than half of studies), with reoperations primarily performed for loose body removal or debridement. CONCLUSIONS: This systematic review of 13 studies suggests that OCA transplantation for cartilage defects allows most athletes to return to sport (range, 75%-82%). Most studies reported improvements in sports-specific patient-reported outcomes at follow-up and reached the minimal clinically important difference. However, the reoperation rate was high in several studies, with a large percentage of patients requiring loose body removal or debridement. The long-term survival of the allografts is largely unknown, but this study suggests OCA transplantation consistently improves function in athletes with chondral injuries. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies.

The Role of Bone Marrow Aspirate Concentrate for the Treatment of Focal Chondral Lesions of the Knee: A Systematic Review and Critical Analysis of Animal and Clinical Studies.

PURPOSE: To summarize currently available data regarding the use of bone marrow aspirate concentrate (BMAC) for the treatment of focal chondral lesions of the knee in experimental animal models and human clinical studies. METHODS: A systematic review searching for the terms "(bone marrow)" AND "(aspirate OR concentrate)" AND "(cartilage OR chondral OR osteochondral)" was performed in the databases PubMed, Cochrane Central Register of Controlled Trials, and Google Scholar regarding the use of BMAC for the treatment of focal chondral lesions of the knee. The inclusion criteria were animal and clinical studies published in English that used autologous BMAC to treat focal chondral defects of the knee. We excluded studies that evaluated nonconcentrated preparations of bone marrow aspirate or preparations that were culture expanded. RESULTS: A total of 23 studies were included: 10 studies performed in animal models and 13 human clinical studies. Animal studies showed inconsistent outcomes regarding the efficacy of BMAC for the treatment of chondral or osteochondral lesions, assessed by gross morphology, second-look arthroscopy, magnetic resonance imaging, histology, immunohistochemistry, mechanical testing, and micro-tomography. Chondral defect filling was achieved with fibrocartilage or "hyaline-like" cartilage. Cells present in BMAC did not meet the criteria to be characterized as mesenchymal stem cells according to the International Society for Cell Therapy because freshly isolated cells failed to show tri-lineage differentiation. Overall, all clinical studies, independent of the study group or level of evidence, reported improved clinical outcomes and higher macroscopic, magnetic resonance imaging, and histology scores. Comparative trials favored BMAC over microfracture and reported equivalent outcomes between BMAC and matrix-induced autologous chondrocyte implantation. However, clinical studies were scant and showed low scientific rigor, poor methodologic quality, and low levels of evidence on average. CONCLUSIONS: Although clinical success in short-term and midterm applications has been suggested for the application of BMAC for the restoration of cartilage defects in lesions of the knee, current study designs are generally of low scientific rigor. In addition, clinical applications of this technology in animal model investigations have shown inconsistent outcomes. Thus, clinicians should apply this technology cautiously. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III, and IV evidence studies.

Cartilage regeneration using a novel autologous growth factors-based matrix for full-thickness defects in sheep.

PURPOSE: To investigate the chondrogenic-regenerative properties of a novel autologous-made matrix composed of hyaline cartilage chips combined with a growth factors-based clot for full-thickness defects in sheep. METHODS: A full-thickness, 8-mm diameter cartilage defect was created in the weight-bearing area of the medial femoral condyle in 6 sheep. Treatment consisted of surgical implantation of an autologous-based matrix of hyaline cartilage chips combined with a clot of plasma poor in platelets and intraarticular injection of plasma rich in growth factors. Outcome measures at 1, 3 and 6 months included macroscopic International Cartilage Repair Society (ICRS) score, histological and immunohistochemical analysis for collagen expression, and transmission electron microscopy study. RESULTS: The 6-month macroscopic evaluation showed nearly normal (11.1 ± 0.7) cartilage repair assessment. The ICRS score was significantly higher at 6 months compared to 3 months (5.5 ± 1.3; p < 0.0001) and 1 (1.1 ± 0.4; p < 0.0001) month. At 6 months, hyaline cartilage tissue filling the defect was observed with adequate integration of the regenerated cartilage at the surrounding healthy cartilage margin. At 6 months, mature chondrons and cartilage matrix contained collagen fibers with masked fibrillary structure, and the expression of collagen in the newly formed cartilage was similar in intensity and distribution pattern compared to the healthy adjacent cartilage. CONCLUSIONS: This novel treatment enhanced chondrogenesis and regenerated hyaline cartilage at 6 months with nearly normal macroscopic ICRS assessment. Histological analysis showed equivalent structure to mature cartilage tissue in the defect and a collagen expression pattern in the newly formed cartilage similar to that found in adjacent healthy articular cartilage. The present technique may have clinical application for chondral injuries in humans because this procedure is cheap (no need for allograft, or expensive instrumentation/biomaterials/techniques), easy and fast-performing through a small arthrotomy, and safe (no rejection possibility because the patients' own tissue, cells, and plasma are used).

Is there a role for stem cells in treating articular injury?

Articular cartilage is a specialized tissue with a high prevalence of injuries. The complex architecture of articular cartilage means that injuries are difficult to treat. The sequelae of such injuries include post-traumatic osteoarthritis. Current treatments include microfracture, microdrilling, osteochondral transplantation and matrix autologous chondral implantation. However, current surgical therapies have a number of disadvantages. Mesenchymal stem cells have been suggested as a potential alternative therapy, with a theoretical ability to regenerate articular cartilage. Research, although positive, is mainly limited to case series, in which the follow up is short to medium term. Stem cells may hold the answer to the age-old problem of articular cartilage injury but more robust evidence is required.

Fresh osteochondral allografts-procurement and tissue donation in Europe.

Fresh osteochondral allografts are a well-established treatment for large, full-thickness cartilage defects. The clinical outcome for carefully selected patients is very favorable, especially for the young and active and graft survival up to 25 years has been described in the literature. Furthermore, a high patient satisfaction rate has been reported, but the biggest obstacle to overcome is the availability of tissue for transplantation. Large fresh bone allografts for cartilage damage repair only can be harvested from organ donors following organ removal or cadaveric donors, preferably in the setting of an operation room to minimize possible contamination of the tissue. Apart from the logistic challenges this entails, an experienced recovery team is needed. Furthermore, the public as well as medical staff is much less aware of the possibility and requirements of tissue donation than organ donation and families of deceased are rarely approached for bone and cartilage donation. This review aims to highlight the current situation of organ and tissue donation in Europe with special focus on the processing of bones and possible safety and quality concerns. We analyze what may prevent consent and what might be done to improve the situation of tissue donation.

Is There Any Correlation Between Short-Term MRI And Mid-Term Clinical Resultsin Patients Undergoing An Osteochondral Autograft In The Knee?

Thirthy three patients (mean age 32 years) undergoing OA were retrospectively evaluated. All patients had MRI at mean 6.6 months. Lysholm, International Knee Documentation Committee (IKDC), and Tegner scores. The aim is to evaluate Magnetic Resonance Imaging (MRI) in patients who underwent an Osteochondal Autograft (OA) and correlate them with their clinical results-evaluated at mean followup of 28 months (12-88). Tegner Pre-operatively: 6.6, Post-operative: 7.4 (p<0.001). Mean Lysholm: 87, mean IKDC: 86. MRI: complete filling of the lesion in 25 (75.7%) patients, complete integration of the graft in 5 (15.1%) and intact repair tissue in 22 (66.6%. Positive correlation between the degree of repair and filling of the defect and higher Lysholm and IKDC (p<0.05). There is a minor association between short-term MRI and mid-term clinical results after an OA being the degree of repair and filling of the chondral defect the only parameters correlated with patient´s evolution.

Osteochondral Autograft Transplantation: A Review of the Surgical Technique and Outcomes.

Isolated chondral and osteochondral defects of the knee are challenging clinical entities, particularly in younger patients. Cartilage treatment strategies have previously been characterized as palliation (ie, chondroplasty and debridement), repair (ie, drilling and microfracture), or restoration (ie, autologous chondrocyte implantation, osteochondral autograft, and osteochondral allograft). The osteochondral autograft transplantation procedure allows defects to be filled immediately with mature, hyaline articular cartilage by utilizing either an arthroscopic or a mini-open procedure. Graft harvest and placement can be technically demanding, but results show trends toward greater longevity, durability, and improved outcomes in high-demand patients when compared with alternative techniques. Improved results are shown in younger patients with isolated lesions between 1 and 4 cm.

Osteochondral Allograft Transplantation in the Knee.

The technique of osteochondral allograft (OCA) transplantation has been used to treat a wide spectrum of cartilage deficiencies in the knee. Its use has been supported by basic science and clinical studies that show it is a safe and effective treatment option. What sets fresh OCA transplantation apart from other cartilage procedures in the knee, is the ability to treat large defects with mature hyaline cartilage. Studies looking at transplantation of fresh OCAs in the general population have shown reliable pain relief and return to activities of daily living. Reports of cartilage injuries in athletes have risen over the years and more research is needed in evaluating the successfulness of OCA transplantation in the athletic population.

Autologous Chondrocyte Implantation: Past, Present, and Future.

Focal cartilage defects of the knee are relatively common and may increase the risk of developing osteoarthritis. Autologous chondrocyte implantation (ACI) aims to restore the integrity of isolated cartilage lesions through the induction of hyaline-like cartilage formation. Although ACI has traditionally been used as a second-line treatment, recent evidence suggests that ACI should be considered as a first-line treatment option in certain patients. Recent controlled trials also suggest that there are improved clinical outcomes among those patients who undergo ACI over the mid-term and long-term compared with those treated with microfracture or osteochondral autograft/mosaicplasty, regardless of lesion size. Recent literature also indicates that arthroscopic, second-generation and third-generation techniques are associated with better outcomes and fewer complications than first-generation ACI. In summary, ACI is an effective tool for cartilage restoration that may be more efficacious and durable than other cartilage restoration techniques for appropriate candidates.

Considerations in Evaluating Treatment Options for Patellofemoral Cartilage Pathology.

Patellofemoral (PF) pain, a subset of anterior knee pain, presents a particularly challenging diagnosis due to the multifactorial etiology. Within this group, assigning the patient's symptoms to a patellofemoral cartilage lesion is indirect; that is, a diagnosis by exclusion as hyaline cartilage is aneural. In addition, these PF compartment lesions are often in conjunction with various comorbidities, for example, malalignment and/or instability. In light of these factors and the high shear and compression stresses at the PF compartment, patellar and trochlear chondral lesions require unique treatment considerations from the tibiofemoral compartments. A thorough understanding of the various cartilage restoration techniques available is necessary to select the best option for the individual patient/knee/lesion noting that there is overlap of techniques' applications. In addition, failure to address and correct associated comorbidities may jeopardize the outcome of any cartilage restoration procedure. That is, the key to achieving optimal outcomes with PF cartilage restoration is to select the best cartilage treatment for the particular setting and to concomitantly optimize the PF biomechanical environment and stability.

Mosaicplasty for the treatment of a large traumatic osteochondral femoral head lesion: a case report with 2 year follow-up and review of the literature.

Different joint-preserving techniques have been described for the treatment of traumatic osteochondral lesions of the femoral head especially in young active patients. Mosaicplasty with autologous transplantation of osteochondral cylinders is an established surgical technique in the knee. Little evidence, however, exists for the treatment of osteochondral lesions in the hip using this technique. Here, we report on the result of treatment of a traumatic 5 cm(2) osteochondral lesion of the femoral head in a young patient treated with mosaicplasty. Grafts were taken from the ipsilateral knee. After 2 years, the outcome was satisfactory with partial return to previous activity level.

A preclinical evaluation of an autologous living hyaline-like cartilaginous graft for articular cartilage repair: a pilot study.

In this pilot study, an autologous synthetic scaffold-free construct with hyaline quality, termed living hyaline cartilaginous graft (LhCG), was applied for treating cartilage lesions. Implantation of autologous LhCG was done at load-bearing regions of the knees in skeletally mature mini-pigs for 6 months. Over the course of this study, significant radiographical improvement in LhCG treated sites was observed via magnetic resonance imaging. Furthermore, macroscopic repair was effected by LhCG at endpoint. Microscopic inspection revealed that LhCG engraftment restored cartilage thickness, promoted integration with surrounding native cartilage, produced abundant cartilage-specific matrix molecules, and re-established an intact superficial tangential zone. Importantly, the repair efficacy of LhCG was quantitatively shown to be comparable to native, unaffected cartilage in terms of biochemical composition and biomechanical properties. There were no complications related to the donor site of cartilage biopsy. Collectively, these results imply that LhCG engraftment may be a viable approach for articular cartilage repair.

Use of Interim Scaffolding and Neotissue Development to Produce a Scaffold-Free Living Hyaline Cartilage Graft.

The fabrication of three-dimensional (3D) constructs relies heavily on the use of biomaterial-based scaffolds. These are required as mechanical supports as well as to translate two-dimensional cultures to 3D cultures for clinical applications. Regardless of the choice of scaffold, timely degradation of scaffolds is difficult to achieve and undegraded scaffold material can lead to interference in further tissue development or morphogenesis. In cartilage tissue engineering, hydrogel is the highly preferred scaffold material as it shares many similar characteristics with native cartilaginous matrix. Hence, we employed gelatin microspheres as porogens to create a microcavitary alginate hydrogel as an interim scaffold to facilitate initial chondrocyte 3D culture and to establish a final scaffold-free living hyaline cartilaginous graft (LhCG) for cartilage tissue engineering.

Hyaline cartilage formation and tumorigenesis of implanted tissues derived from human induced pluripotent stem cells.

Induced pluripotent stem cells (iPSCs) are a promising cell source for cartilage regenerative medicine. Meanwhile, the risk of tumorigenesis should be considered in the clinical application of human iPSCs (hiPSCs). Here, we report in vitro chondrogenic differentiation of hiPSCs and maturation of the differentiated hiPSCs through transplantation into mouse knee joints. Three hiPSC clones showed efficient chondrogenic differentiation using an established protocol for human embryonic stem cells. The differentiated hiPSCs formed hyaline cartilage tissues at 8 weeks after transplantation into the articular cartilage of NOD/SCID mouse knee joints. Although tumors were not observed during the 8 weeks after transplantation, an immature teratoma had developed in one mouse at 16 weeks. In conclusion, hiPSCs are a potent cell source for regeneration of hyaline articular cartilage. However, the risk of tumorigenesis should be managed for clinical application in the future.

Talocalcaneal Joint Middle Facet Coalition Resection With Interposition of a Juvenile Hyaline Cartilage Graft.

Talocalcaneal joint middle facet coalition is the most common tarsal coalition, occurring in ≤2% of the population. Fewer than 50% of involved feet obtain lasting relief of symptoms after nonoperative treatment, and surgical intervention is commonly used to relieve symptoms, increase the range of motion, improve function, reconstruct concomitant pes planovalgus, and prevent future arthrosis from occurring at the surrounding joints. Several approaches to surgical intervention are available for patients with middle facet coalitions, ranging from resection to hindfoot arthrodesis. We present a series of 4 cases, in 3 adolescent patients, of talocalcaneal joint middle facet coalition resection with interposition of a particulate juvenile hyaline cartilaginous allograft (DeNovo(®) NT Natural Tissue Graft, Zimmer, Inc., Warsaw, IN). With a mean follow-up period of 42.8 ± 2.9 (range 41 to 47) months, the 3 adolescent patients in the present series were doing well with improved subtalar joint motion and decreased pain, and 1 foot showed no bony regrowth on a follow-up computed tomography scan. The use of a particulate juvenile hyaline cartilaginous allograft as interposition material after talocalcaneal middle facet coalition resection combined with adjunct procedures to address concomitant pes planovalgus resulted in good short-term outcomes in 4 feet in 3 adolescent patients.