ArticleLiterature Review

Microfracture: Surgical Technique and Rehabilitation to Treat Chondral Defects

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Abstract

Full-thickness articular cartilage defects rarely heal spontaneously. Some patients may not have clinically significant problems from chondral defects, but most eventually have degenerative changes. Techniques to treat chondral defects include abrasion, drilling, autografts, allografts, and cell transplantation. The senior author (JRS) developed the microfracture technique to enhance chondral resurfacing by providing a suitable environment for new tissue formation and taking advantage of the body's own healing potential. Microfracture has been done in more than 1800 patients. Specially designed awls are used to make multiple perforations, or microfractures, into the subchondral bone plate. Perforations are made as close together as possible, but not so close that one breaks into another. They usually are approximately 3 to 4 mm apart. The integrity of the subchondral bone plate must be maintained. The released marrow elements (including mesenchymal stem cells, growth factors, and other healing proteins) form a surgically induced super clot that provides an enriched environment for new tissue formation. The rehabilitation program is crucial to optimize the results of the surgery. It promotes the ideal physical environment for the marrow mesenchymal stem cells to differentiate into articular cartilagelike cells, ultimately leading to development of a durable repair cartilage that fills the original defect.

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... Several conservative options have been proposed to reduce pain and restore articular function; besides a wide array of surgical techniques (abrasive chondroplasty, microfracture, and spongialisation) have been proposed for the management of chondral lesions [3,4]. ...
... Repair and regeneration of articular cartilage is a significant challenge for orthopedic surgeons: traditional stimulation treatments (microfractures or osteochondral substitutes) can enhance knee function by stimulating a spontaneous repair reaction but they cannot restore a cartilage structure histologically resembling native tissue [4,18,19]. e tissue formed is variable in composition and durability. ese treatment modalities are usually unsatisfactory in the long term, and eventually fail since fibrocartilage develops in the long term, rather than the desired hyaline cartilage [4,20]. ...
... e tissue formed is variable in composition and durability. ese treatment modalities are usually unsatisfactory in the long term, and eventually fail since fibrocartilage develops in the long term, rather than the desired hyaline cartilage [4,20]. ...
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Background. This study aims to compare the effects of platelet-rich plasma (PRP) alone or in combination with adipose-derived mesenchymal stem cells (AD-MSCs) in patients affected by cartilage defects, undergoing knee arthroscopic microfracture. Methods. Thirty-eight patients diagnosed with a knee monocompartmental cartilage defect (Outerbridge grade IV) on the MRI, underwent an arthroscopic procedure. After the confirmation of the lesion, they all received the same bone marrow stimulation technique (microfracture) and were randomized into two groups: the first one had additional PRP injection (group A), while the second received PRP and AD-MSC injection (group B). Knee assessment and pain score were documented with Knee Injury Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) score, Short-Form (SF) 12, and Visual Analogue Scale (VAS) before the treatment and at 1, 3, 6, and 12 months of follow-up postoperatively. An additional arthroscopic procedure, performed in four patients for a subsequent meniscal lesion, let us evaluate cartilage evolution by performing a macro/microscopical assessment on cartilage biopsy specimens. Results. At the 12-month follow-up, both groups showed a comparable functional improvement. The scores on the IKDC form, KOOS, pain VAS, and SF-12 significantly improved from baseline (p
... Marrow stimulation which encompasses abrasive sub-chondroplasty, microfracture, or subchondral drilling aims at brining bleeding through the subchondral plate in the area of cartilage injury with the end goal of relocating mesenchymal stem cells into the area of injury. [277][278][279] This migration coalesces with formation of a clot in the cartilage defect and eventual development of Type I fibrocartilage to replace the Type II hyaline defect. 278 Historically microfracture has shown good short-to-midterm outcomes specifically for younger patients with smaller (~1 cm 2 ) isolated lesions, but more recent reviews have called into question failure rates, arthritic progression, and return to sport rates. ...
... [277][278][279] This migration coalesces with formation of a clot in the cartilage defect and eventual development of Type I fibrocartilage to replace the Type II hyaline defect. 278 Historically microfracture has shown good short-to-midterm outcomes specifically for younger patients with smaller (~1 cm 2 ) isolated lesions, but more recent reviews have called into question failure rates, arthritic progression, and return to sport rates. 280, 281 The biomechanical deterioration of fibrocartilage at 2 years when placed under the cyclic load experience at the joint surface is the impotence behind this concern. ...
Article
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Knee pain is second only to the back as the most commonly reported area of pain in the human body. With an overall prevalence of 46.2%, its impact on disability, lost productivity, and cost on healthcare cannot be overlooked. Due to the pervasiveness of knee pain in the general population, there are no shortages of treatment options available for addressing the symptoms. Ranging from physical therapy and pharmacologic agents to interventional pain procedures to surgical options, practitioners have a wide array of options to choose from - unfortunately, there is no consensus on which treatments are "better" and when they should be offered in comparison to others. While it is generally accepted that less invasive treatments should be offered before more invasive ones, there is a lack of agreement on the order in which the less invasive are to be presented. In an effort to standardize the treatment of this extremely prevalent pathology, the authors present an all-encompassing set of guidelines on the treatment of knee pain based on an extensive literature search and data grading for each of the available alternative that will allow practitioners the ability to compare and contrast each option.
... The second key finding that extended subchondral bone changes after defect debridement is also clinically relevant. Such alterations are a common and potentially serious 14,55 problem after marrow stimulation, seen in one-third of treated patients 8,22,30,31,48 and in preclinical models. 4,11,14,37,39,41 The osseous repair of drill holes follows a defined bone remodeling sequence usually resulting in incomplete reconstitution of the normal subchondral bone microstructure 6,10,41 and in morphological alterations. ...
... Such subchondral bone changes including intralesional osteophytes possibly deteriorate long-term results of marrow stimulation by disturbing the functional integrity of the osteochondral unit. 8,14,29,30,37,55 In sum, drilling reduced potentially detrimental effects on the subchondral bone compared with debridement as indicated by a more physiological BMD and smaller osteophytes. ...
Article
Background Subchondral drilling is an established marrow stimulation technique for small cartilage defects, but whether drilling is required at all and if the drill hole density affects repair remains unclear. Hypotheses Osteochondral repair is improved when the subchondral bone is perforated by a higher number of drill holes per unit area, and drilling is superior to defect debridement alone. Study Design Controlled laboratory study. Methods Rectangular full-thickness chondral defects (4 × 8 mm) were created in the trochlea of adult sheep (N = 16), debrided down to the subchondral bone plate without further treatment as controls (no treatment; n = 7) or treated with either 2 or 6 (n = 7 each) subchondral drill holes (diameter, 1.0 mm; depth, 10.0 mm). Osteochondral repair was assessed at 6 months postoperatively by standardized (semi-)quantitative macroscopic, histological, immunohistochemical, biochemical, and micro–computed tomography analyses. Results Compared with defect debridement alone, histological overall cartilaginous repair tissue quality ( P = .025) and the macroscopic aspect of the adjacent cartilage ( P≤ .032) were improved after both drilling densities. Only drilling with 6 holes increased type 2 collagen content in the repair tissue compared with controls ( P = .038). After debridement, bone mineral density was significantly decreased in the subchondral bone plate ( P≤ .015) and the subarticular spongiosa ( P≤ .041) compared with both drilling groups. Debridement also significantly increased intralesional osteophyte sectional area compared with drilling ( P≤ .034). No other differences in osteochondral repair existed between subchondral drilling with 6 or 2 drill holes. Conclusion Subchondral drilling independent of drill hole density significantly improves structural cartilage repair compared with sole defect debridement of full-thickness cartilage defects in sheep after 6 months. Subchondral drilling also leads to a better reconstitution of the subchondral bone compartment below the defects. Simultaneously, drilling reduced the formation of intralesional osteophytes caused by osseous overgrowth compared with debridement. Clinical Relevance These results have important clinical implications, as they support subchondral drilling independent of drill hole number but discourage debridement alone for the treatment of small cartilage defects. Clinical studies are warranted to further quantify the effects of subchondral drilling in similar settings.
... The standard method of application is by injection into the knee joint cavity, but PRP spreads to the entire joint cavity, and the therapeutic effect is limited [4]. Microfractures can also be used to treat cartilage defects by stimulating bone marrow to promote cartilage production [5,6]. Studies have shown that PRP injection combined with microfracture can enhance the repair response of cartilage defects [7]. ...
... Microfracture is a method of drilling the subchondral bone evenly and vertically to form a rough surface, which allows a haematoma to adhere and fill the defect. Potential stem cells infiltrating the bone marrow can differentiate into fibrochondrocytes and repair cartilage defects [5,10]. Namdari et al. [11] treated 24 American Basketball Association athletes for knee cartilage injuries using microfractures and conducted Fig. 1 Images from typical cases. ...
Article
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Purpose An investigation of arthroscopic surgery combined with coverage of the microfractured wound surface with platelet-rich plasma (PRP) and fibrin gels (FG) to treat knee cartilage defects. Methods Between February 2017 and February 2020, 145 patients with knee cartilage defects were treated. Only isolated full-thickness cartilage defects were included, and 28 patients (12 men and 16 women) were included in this study. They were all treated with arthroscopic surgery on subchondral bones, filled with PRP and thrombin, and sealed with FG. The knee pain visual analogue scale (VAS) scores were measured after the patients climbed ten stairs up and down, and the Western Ontario and McMaster Universities osteoarthritis index and the area of cartilage defects were measured through the pre-operative and post-operative follow-up. The complication incidences were also observed. Results All patients were followed up for ten to 15 months (median 12 months). The knee pain VAS scores decreased from 6.57 ± 1.07 pre-operatively to 2.09 ± 1.35 at the last follow-up. The WOMAC osteoarthritis index decreased from 44.32 ± 3.95 (mean ± sd) pre-operatively to 16.57 ± 2.20 by the last follow-up. The cartilage defect decreased from 2.93 ± 0.65 cm ² pre-operatively to 1.09 ± 0.69 cm ² at the last follow-up. All scores showed statistically significant improvements after surgery ( p < 0.05). No complications were observed. Conclusion The combination therapy of arthroscopic surgery and covering the microfractured wound surface with PRP and FG can repair knee cartilage defects, relieve pain, and improve function, and is a safe and effective treatment.
... The first 576 most-cited results were reviewed and screened according to the previously described inclusion and exclusion criteria, to determine the Top 50 clinical articles on cartilage surgery. The number of citations of the 50 most-cited clinical articles on cartilage surgery ranged from 4211 to 239 with a mean of 503.5 citations (Table 1) [2-5, 7, 8, 11, 14, 16, 22, 23, 25, 27, 29-34, 36-38, 40, 42, 46, 48-50, 53, 54, 56, 59-61, 63-68, 72, 74, 75, NA not applicable [80][81][82][83][86][87][88]. These articles have been collectively cited 25,177 times at the time of the search. ...
... Among the Top 50 list, microfractures represent the second technique with more interest in this field. This reparative procedure, introduced in the surgical practice by Steadman in the early 1980s, is still the most common first-line option for small cartilage lesions [83]. This is due to the minimal invasiveness, simplicity of execution, single-stage procedure, limited costs, and large availability [76]. ...
Article
PurposeArticular cartilage lesions remain a challenge for orthopedic surgeons. The identification of the most important articles can help identifying the most influential techniques of the past, the current prevalent focus, and emerging strategies. The aim of this study was to identify milestones and trends in cartilage research. Methods This study is a bibliometric analysis based on published articles. All citation count data included in the “Scopus database” were used to identify eligible studies up to December 2020. The 50 most-cited articles on cartilage surgery were ranked based on the citation count and analyzed regarding citation density and quality (Coleman score and RoB 2.0 tool). A further search was performed to identify the most promising clinical studies among the latest publications on cartilage surgery. ResultsDifferent kinds of cartilage treatments were investigated in the 50 most-cited clinical articles. Regenerative techniques with chondrocytes were the most reported with a total of 23 articles, followed by microfracture technique in 17 articles and mosaicplasty or osteochondral autograft transplantation (OAT) in 11. Forty-five articles focused on the knee. A higher citation density was found in the most recent articles (p = 0.004). The study of the most promising landmarks of the most recent articles showed new cell-free or tissue engineering-based procedures and an overall increasing quality of the published studies. Conclusion This bibliometric analysis documented an increasing interest in cartilage surgery, with efforts toward high-quality studies. Over the years, the focus switched from reconstructive toward regenerative techniques, with emerging options including cell-free and tissue-engineering strategies to restore the cartilage surface.Level of evidenceIV.
... [54] Bin dokuz yüz seksenlerde Steadman tarafından önerilen ilk kullanımdan bu yana, mikrokırık kondral lezyonların yönetimi için tercih edilen tedavi hâline gelmiştir. [57] Teknik, kıkırdak, kemik, tendon ve bağlar dâhil olmak üzere çeşitli bağ dokularına farklılaşma potansiyeli yüksek olan subkondral kemiğin mezenkimal kök hücrelerininlerinin doğrudan uyarılmasına dayanmaktadır. [58,59] Mezenkimal kök hücrelerin rejeneratif etkileri, doğrudan hücreden hücreye etkileşim veya biyoaktif bileşenlerin salgılanması yoluyla doku onarımını ve inflamasyonun çözülmesini teşvik etmedeki amaçlarını sağlar. ...
... Microfracture is a minimally invasive technique that uses an arthroscope to drill small, equidistant holes in subchondral bone, at least 3-4 mm apart and 4 mm in depth, with 3-4 holes per a 1 cm area [12]. This procedure induces the migration of MSCs from the bone marrow to the cartilage defect to allow the formation of fibrocartilage [13]. ...
Article
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Microfracture is a common technique that uses bone marrow components to stimulate cartilage regeneration. However, the clinical results of microfracture range from poor to good. To enhance cartilage healing, several reinforcing techniques have been developed, including porcine-derived collagen scaffold, hyaluronic acid, and chitosan. Autologous collagen-induced chondrogenesis (ACIC) is a single-step surgical technique for cartilage regeneration that combines gel-type atelocollagen scaffolding with microfracture. Even though ACIC is a relatively new technique, literature show excellent clinical results. In addition, all procedures of ACIC are performed arthroscopically, which is increasing in preference among surgeons and patients. The ACIC technique also is called the Shetty–Kim technique because it was developed from the works of A.A. Shetty and S.J. Kim. This is an up-to-date review of the history of ACIC.
... To date, most knee surgeons prefer microfracturing as the favourite marrow stimulating technique, which was popularized by Steadman and is commonly seen as an enhancement/advancement of subchondral drilling proposed by Pridie in 1959 (26,36). It is easy to perform, and there is no risk of thermal necrosis. ...
Article
Background/aim: Common surgical treatment options for large focal chondral defects (FCDs) in the knee include microfracturing (MFX) and microdrilling (DRL). Despite numerous studies addressing MFX and DRL of FDCs, no in vivo study has focused on biomechanical analysis of repair cartilage tissue in critical size FCDs with different amounts of holes and penetration depths. Materials and methods: Two round FCDs (d=6 mm) were created on the medial femoral condyle in 33 adult merino sheep. All 66 defects were randomly assigned to 1 control or 4 different study groups: 1) MFX1, 3 holes, 2 mm depth; 2) MFX2, 3 holes, 4 mm depth; 3) DRL1, 3 holes, 4 mm depth; and 4) DRL2, 6 holes, 4 mm depth. Animals were followed up for 1 year. Following euthanasia, quantitative optical analysis of defect filling was performed. Biomechanical properties were analysed with microindentation and calculation of the elastic modulus. Results: Quantitative assessment of defect filling showed significantly better results in all treatment groups compared to untreated FCDs in the control group (p<0.001), with the best results for DRL2 (84.2% filling). The elastic modulus of repair cartilage tissue in the DRL1 and DRL2 groups was comparable to the adjacent native hyaline cartilage, while significantly inferior results were identified in both MFX groups (MFX1: p=0.002; MFX2: p<0.001). Conclusion: More defect filling and better biomechanical properties of the repair cartilage tissue were identified for DRL compared to MFX, with the best results for 6 holes and 4 mm of penetration depth. These findings are in contrast to the current clinical practice with MFX as the gold standard and suggest a clinical return to DRL.
... During recent decades, several approaches to articular cartilage repair have been established. Bone 2 of 9 marrow stimulation [2], osteochondral transplantation [3] and autologous chondrocyte transplantation (ACT) [4] are the most commonly used and most discussed methods. Continuously, innovative therapy options are developed based on enhancements of these fundamental techniques [5]. ...
Article
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Background and Objective: Translational large animal models are inevitable to transfer cartilage repair methods into clinical practice. Guidelines for these trials have been published by guiding agencies (FDA, ASTM, EMEA) including recommendations for study descriptors and study outcomes. However, practical adherence to these recommendations is not achieved in all aspects. This study includes an assessment of the recommended aspects regarding practical relevance in large animal models for cartilage repair by professionals in the field. Materials and Methods: In an online based survey, 11 aspects regarding study design and 13 aspects regarding study outcome from previously published guidelines were evaluated (0–10 points, with 10 being most important) by study participants. Additionally, the survey contained questions related to professional experience (years), professional focus (preclinical, clinical, veterinarian, industry) and the preferred translational large animal model for cartilage repair. Results: The total number of survey participants was 37. Rated as most important for study design parameters was lesion size (9.54 pts., SD 0.80) followed by study duration (9.43 pts., SD 1.21); and method of scaffold fixation (9.08 pts., SD 1.30) as well as depth of the lesion (9.03 pts., SD 1.77). The most important aspects of study outcome were considered histology (9.41 pts., SD 0.86) and defect filling (8.97 pts., SD 1.21), while gene expression was judged as the least important (6.11 pts., SD 2.46) outcome. A total of 62.2% of all participants were researchers, 18.9% clinicians, 13.5% veterinarians and 5.4% industry employees. Conclusions: In translational research, recommendations published by guiding agencies receive broad theoretical consensus within the community, including both clinically and preclinically orientated scientists. However, implementation into practical research lacks in major aspects. Ongoing re-evaluation of the guidelines under involvement of all stakeholders and approaches to overcome financial and infrastructural limitations could support the acceptance of the guidance documents and contribute to standardization in the field.
... First described in the 1990s, the microfracture procedure was initially performed on the knee as an articular cartilage strategy to treat large cartilage defects. 48 It involved specialized instruments to release progenitor cells from bone marrow beneath the subchondral plate to permeate a chondral lesion, clot, and promote new bone repair. The strongest data regarding the effectiveness of microfracture may stem from the knee as large studies with midterm outcomes are available. ...
Article
Purpose To report minimum 10-year follow-up survivorship, defined as non-conversion to total hip arthroplasty (THA), and patient-reported outcome scores (PROS) following primary hip arthroscopy with acetabular microfracture in the setting of femoroacetabular impingement syndrome (FAIS) and acetabular chondral lesions, respectively. Methods Data were prospectively collected and retrospectively analyzed on all patients who underwent a primary hip arthroscopy and received an acetabular microfracture between June 2009 and January 2011. Patients with a minimum 10-year follow-up for the modified Harris Hip Score (mHHS), Nonarthritic Hip Score (NAHS), and the visual analog scale (VAS) for pain were included. If available, the minimum 10-year follow-up for the Hip Outcome Score-Sport-Specific Subscale (HOS-SSS) was reported. The demographics, intraoperative findings, surgical procedures, PROS, rate of achieving the minimal clinical important difference (MCID), and secondary surgeries were analyzed and reported. Results Twenty-two hips (20 patients) were included in the study, and the mean follow-up time was 124.5 ± 2.2 months. There were 17 hips (77.3%) from males and 5 hips (22.7%) from females. The average patient age at the time of surgery was 42.3 years ± 9.6. All patients on average experienced statistically significant improvement (P < 0.05) between preoperative and minimum 10-year follow-up scores for all PROs. In total, 77.3% of the patients did not require conversion to THA. Additionally, 83.3% of the patients achieved the MCID for the mHHS, NAHS, and VAS for pain. Conclusion At a minimum 10-year follow-up, survivorship of 77.3% was reported for patients that underwent primary hip arthroscopy with acetabular microfracture for the treatment of FAIS and focal/full-thickness acetabular cartilage lesions. Further, in the patients that did not require THA conversion, significant improvement in all PROS was demonstrated. Level of Evidence IV, Case-Series study.
... Restoring impaired osteochondral structure is clinically challenging, especially for large defects (defined as >3 cm 2 ) in hips. Although various surgical techniques have been developed, most are only applicable to the knee and ankle, and not the hip 14,15 . A previous study suggested that up to 40% of hips with small chondral defects treated with microfracture subsequently require hip replacement 16,17 . ...
Article
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Background: There is currently no ideal treatment for osteochondral lesions of the femoral head (OLFH) in young patients. Methods: We performed a 1-year single-arm study and 2 additional years of follow-up of patients with a large (defined as >3 cm2) OLFH treated with insertion of autologous costal cartilage graft (ACCG) to restore femoral head congruity after lesion debridement. Twenty patients ≤40 years old who had substantial hip pain and/or dysfunction after nonoperative treatment were enrolled at a single center. The primary outcome was the change in Harris hip score (HHS) from baseline to 12 months postoperatively. Secondary outcomes included the EuroQol visual analogue scale (EQ VAS), hip joint space width, subchondral integrity on computed tomography scanning, repair tissue status evaluated with the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, and evaluation of cartilage biochemistry by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) and T2 mapping. Results: All 20 enrolled patients (31.02 ± 7.19 years old, 8 female and 12 male) completed the initial study and the 2 years of additional follow-up. The HHS improved from 61.89 ± 6.47 at baseline to 89.23 ± 2.62 at 12 months and 94.79 ± 2.72 at 36 months. The EQ VAS increased by 17.00 ± 8.77 at 12 months and by 21.70 ± 7.99 at 36 months (p < 0.001 for both). Complete integration of the ACCG with the bone was observed by 12 months in all 20 patients. The median MOCART score was 85 (interquartile range [IQR], 75 to 95) at 12 months and 75 (IQR, 65 to 85) at the last follow-up (range, 24 to 38 months). The ACCG demonstrated magnetic resonance properties very similar to hyaline cartilage; the median ratio between the relaxation times of the ACCG and recipient cartilage was 0.95 (IQR, 0.90 to 0.99) at 12 months and 0.97 (IQR, 0.92 to 1.00) at the last follow-up. Conclusions: ACCG is a feasible method for improving hip function and quality of life for at least 3 years in young patients who were unsatisfied with nonoperative treatment of an OLFH. Promising long-term outcomes may be possible because of the good integration between the recipient femoral head and the implanted ACCG. Level of evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
... An intact smooth cartilage layer is vital for pain-free movement of synovial joints, however, the ability of the articular cartilage to self-repair when damaged is limited. Small cartilage lesions are typically addressed surgically through marrow stimulation techniques such as microfracture or drilling [2] , although the newly generated tissue has been reported to be fibro-as opposed to hyaline cartilage and thus may not result in long-lasting repair [ 3 , 4 ]. Larger cartilage lesions are often treated using approaches such as osteochondral autograft transplantation (OAT), whereby an osteochondral plug (or plugs in the case of mosaicplasty) is harvested from a non-load bearing part of the joint and implanted into the defect site [ 5 , 6 ]. ...
Article
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Cartilage has poor regenerative capacity and thus damage to the joint surfaces presents a major clinical challenge. Recent research has focussed on the development of tissue-engineered and cell-based approaches for the treatment of cartilage and osteochondral injuries, with current clinically available cell-based approaches including autologous chondrocyte implantation and matrix-assisted autologous chondrocyte implantation. However, these approaches have significant disadvantages due to the requirement for a two-stage surgical procedure and an in vitro chondrocyte expansion phase which increases logistical challenges, hospital times and costs. In this study, we hypothesized that seeding biomimetic tri-layered scaffolds, with proven regenerative potential, with chondrocyte/infrapatellar fat pad stromal cell co-cultures would improve their regenerative capacity compared to scaffolds implanted cell-free. Rapid cell isolation techniques, without the requirement for long term in vitro culture, were utilised to achieve co-cultures of chondrocytes and stromal cells and thus overcome the limitations of existing cell-based techniques. Cell-free and cell-seeded scaffolds were implanted in osteochondral defects, created within the femoral condyle and trochlear ridge, in a translational large animal goat model. While analysis showed trends towards delayed subchondral bone healing in the cell-seeded scaffold group, by the 12 month timepoint the cell-free and cell-seeded groups yield cartilage and bone tissue with comparable quality and quantity. The results of the study reinforce the potential of the biomimetic tri-layered scaffold to repair joint defects but failed to demonstrate a clear benefit from the addition of the CC/FPMSC co-culture to this scaffold. Taking into consideration the additional cost and complexity associated with the cell-seeded scaffold approach, this study demonstrates that the treatment of osteochondral defects using cell-free tri-layered scaffolds may represent a more prudent clinical approach.
... OA has a considerable economic impact on the equine industry, with the annual direct and indirect costs amounting to over $1 billion per year in the United States (7,8). There is no cure for OA and treatment primarily revolves around managing symptoms by systemic and local pharmacological therapies including analgesics and non-steroidal anti-inflammatory agents (NSAIDs) (9), surgical approaches such as microfracture and chondroplasty (10)(11)(12)(13), and regenerative medicine strategies using blood derived (ACS, APS, and PRP) (14-17) or cellbased approaches (ACI/MACI) (18)(19)(20)(21)(22). However, these are only effective at providing short-term relief and do not alter disease progression nor do they completely restore cartilage structure and function (4,23). ...
Article
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With an intrinsically low ability for self-repair, articular cartilage injuries often progress to cartilage loss and joint degeneration resulting in osteoarthritis (OA). Osteoarthritis and the associated articular cartilage changes can be debilitating, resulting in lameness and functional disability both in human and equine patients. While articular cartilage damage plays a central role in the pathogenesis of OA, the contribution of other joint tissues to the pathogenesis of OA has increasingly been recognized thus prompting a whole organ approach for therapeutic strategies. Gene therapy methods have generated significant interest in OA therapy in recent years. These utilize viral or non-viral vectors to deliver therapeutic molecules directly into the joint space with the goal of reprogramming the cells' machinery to secrete high levels of the target protein at the site of injection. Several viral vector-based approaches have demonstrated successful gene transfer with persistent therapeutic levels of transgene expression in the equine joint. As an experimental model, horses represent the pathology of human OA more accurately compared to other animal models. The anatomical and biomechanical similarities between equine and human joints also allow for the use of similar imaging and diagnostic methods as used in humans. In addition, horses experience naturally occurring OA and undergo similar therapies as human patients and, therefore, are a clinically relevant patient population. Thus, further studies utilizing this equine model would not only help advance the field of human OA therapy but also benefit the clinical equine patients with naturally occurring joint disease. In this review, we discuss the advancements in gene therapeutic approaches for the treatment of OA with the horse as a relevant patient population as well as an effective and commonly utilized species as a translational model.
... 17:415 Chondral defects may cause persistent pain, reducing the quality of life, and sport participation, and may predispose to early onset osteoarthritis [1,3]. Microfractures have been proposed for lesions up to 2.5 cm 2 [5][6][7]. For larger defects, autologous chondrocyte implantation (ACI) has been proposed [3,8]. ...
Article
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Background: The efficacy and safety profile of mesenchymal stem cells (MSCs) augmentation in chondral procedures are controversial. This systematic review updated the current evidence on MSCs augmentation for chondral procedures in patients with symptomatic chondral defects of the knee. Methods: This study followed the PRISMA guidelines. The literature search was updated in August 2022. Two independent authors accessed PubMed, Google scholar, Embase, and Scopus. No additional filters or time constrains were used for the search. A cross reference of the bibliographies was also performed. All the clinical studies investigating surgical procedures for chondral defects of the knee augmented with MSCs were accessed. Defects of both tibiofemoral and patellofemoral joints were included. The following patient reported outcomes measures (PROMs) were retrieved at baseline and last follow-up: Visual Analogic Scale (VAS), Tegner Activity Scale, Lysholm Knee Scoring System, International Knee Documentation Committee (IKDC). Return to daily activities and data on hypertrophy, failure, revision surgery were also collected. Failures were defined as the recurrence of symptoms attributable to the index procedure. Revisions were defined as any reoperation at the site of the index procedure. Results: A total of 15 clinical studies (411 procedures) were included. Patients returned to their prior sport activity at 2.8 ± 0.4 months. All the PROMs improved at last follow-up: Tegner (P = 0.0002), Lysholm (P < 0.0001), the IKDC (P < 0.0001), VAS (P < 0.0001). At a mean of 30.1 ± 13.9 months, 3.1% (2 of 65 patients) reported graft hypertrophy, 3.2% (2 of 63) were considered failures. No surgical revision procedures were reported. Given the lack of available quantitative data for inclusion, a formal comparison of surgical procedures was not conducted. Conclusion: MSCs augmentation in selected chondral procedures could be effective, with a low rate of complications. Further investigations are required to overcome the current limitations to allow the clinical translation of MSCs in regenerative medicine.
... In microfracture, an arthroscopic awl is used to drill multiple small holes in the subchondral bone which leads to super clot formation. This provides suitable environment for the pluripotential marrow stem cells to differentiate into fibrocartilaginous repair tissue that fills the original defect [14]. ...
Article
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Osteoarthrosis is the most common form of knee arthritis, characterized by pain and discomfort from primarily articular cartilage wear. Traditionally in its end stage, it has been treated with total knee arthroplasty, a permanent process with a life span of ten to fifteen years and challenges with revision. With an increasing longevity and epidemic of obesity that the population is facing, naturally, we are seeing more and more patients with osteoarthrosis at a younger age. This makes it imperative to extend the life of the native knee by conservative measures, injections of steroid, hyaluronic acid, or biologicals and finally a slew of surgical alternatives ranging from joint realignment to partial and total joint replacement. Besides the clinical presentation, decisions are made based on joint alignment, extent and degree of cartilage wear and the status of the subchondral bone. Imaging plays an invaluable role in surgical decision making. In this article, we will discuss how imaging is used in our practice during decision making for the management of the young osteoarthritic knee.
... The rehabilitation program will be the based on the treatment received (MACI or microfracture). Guidance for rehabilitation following MACI is based on Ebert 2017 publication [24] and that for microfracture is based on Steadman 2001 [25]. Both programs are staged to promote a progressive return to full joint range of motion and weight bearing as well as muscle strengthening and conditioning. ...
... For example, non-surgical approaches include intra-articular injections of various compounds [6], hyaluronic acid (HA) [7], and platelet-rich plasma [8]. The surgical approaches include micro-fracture [9], osteochondral allograft [10] or allografting, matrix-induced autologous chondrocyte implantation [11][12][13][14], and cartilage tissue engineering (CTE) [15]. ...
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An osteochondral defect is a common and frequent disease in orthopedics and treatment effects are not good, which can be harmful to patients. Hydrogels have been applied in the repair of cartilage defects. Many studies have reported that hydrogels can effectively repair osteochondral defects through loaded cells or non-loaded cells. As a new type of hydrogel, photo-crosslinked hydrogel has been widely applied in more and more fields. Meanwhile, 3D bioprinting serves as an attractive platform to fabricate customized tissue-engineered substitutes from biomaterials and cells for the repair or replacement of injured tissues and organs. Although photo-crosslinkable hydrogel-based 3D bioprinting has some advantages for repairing bone cartilage defects, it also has some disadvantages. Our aim of this paper is to review the current status and prospect of photo-crosslinkable hydrogel-based 3D bioprinting for repairing osteochondral defects.
... In this method, the primary goal of making small holes on subchondral bone is to release the bone marrow and form a marrow clot, and the secondary goal is to make a rough surface to hold the clot. The formed marrow blood clots contain bone marrow mesenchymal stem cells (BMSCs) and growth factors, the BMSCs can differentiate into chondrocytes and form fibrous cartilage tissue to repair the defected cartilage [15,16]. Low cost, short-term good outcomes, and easy operation make MF being considered the gold standard and the first-line treatment for the cartilage repair by some [17,18]. ...
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Hyaline cartilage plays a critical role in maintaining joint function and pain. However, the lack of blood supply, nerves, and lymphatic vessels greatly limited the self-repair and regeneration of damaged cartilage, giving rise to various tricky issues in medicine. In the past 30 years, numerous treatment techniques and commercial products have been developed and practiced in the clinic for promoting defected cartilage repair and regeneration. Here, the current therapies and their relevant advantages and disadvantages will be summarized, particularly the tissue engineering strategies. Furthermore, the fabrication of tissue-engineered cartilage under research or in the clinic was discussed based on the traid of tissue engineering, that is the materials, seed cells, and bioactive factors. Finally, the commercialized cartilage repair products were listed and the regulatory issues and challenges of tissue-engineered cartilage repair products and clinical application would be reviewed.
... A study showed that within poly (L-lactic acid) (PLLA) scaffolds, collagen matrix or collagen gel prompted chondrocytes to regenerate cartilage expressing type II collagen [33,34]. Alginate beads stimulated chondrogenesis of ingrowing cells while preserving the original scaffold shape, according to Marijnissen et al. [35]. Gelatin has recently been widely used as a carrier for bioactive molecules such as TGF-β and FGF-2 in cartilage tissue engineering [36,37]. ...
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Scaffolds for tissue engineering are support structures that help cells grow and multiply after being implanted into a patient. To allow cellular adhesion, proliferation, and differentiation, the optimal scaffolds should have the right surface chemistry and microstructures. Furthermore, the scaffolds must have sufficient mechanical strength and a low rate of biodegradation with no unwanted by-products. Regenerative medicine efforts currently rely on the transplantation of cells in combination with supporting scaffolds and macromolecules to restore pathologically damaged tissue architectures. Biologically active scaffolds, which are based on analogues of the extracellular matrix that have spurred tissue and organ creation, have attracted a lot of attention in recent years. A scaffold is required to restore function or regenerate tissue, as it will serve as a temporary matrix for cell proliferation and extracellular matrix deposition, with further ingrowth until the tissues are completely restored or regenerated. Different technologies have been employed for fabrication of scaffolds for regeneration of different organs and tissues like skin, cartilage, bone, heart, lungs, liver and kidney. This review focuses on the different strategies used to construct the scaffold for the above-mentioned tissues and organs along with their commercial applications.
... 22 , 27 However, in athletes, a stricter definition is utilized, and microfracture should not be performed on lesions with a diameter greater than 2 cm. 21 In all patients, microfracture is contraindicated in persons unwilling or unable to follow the rehabilitation protocol, 25 , 26 and for the treatment of larger or uncontained cartilage lesions. 22 Additionally, at the time of surgery, any concomitant pathology, such as instability or ligamentous injury should be addressed. ...
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Introduction The prevalence of focal cartilage defects in elite athletes is estimated to be as high as 36%, and treatment in professional football players poses a complex clinical challenge. Marrow stimulation is a common treatment option for athletes with symptomatic, contained, full-thickness chondral injuries. Objectives To report the current indications for and efficacy of marrow stimulation in football players. Methods PubMed, Scopus, and Embase were searched. All levels of evidence (I-IV) pertaining to marrow stimulation in football players were analyzed and presented in a narrative review. Results Reported return to sport rates following microfracture range from 52% to 95%, with up to 67% of athletes returning to preinjury level of performance. Clinical outcomes improve shortly after microfracture but may decline by 2 years postoperatively. Augmented marrow stimulation techniques have since been developed in an effort to improve repair quality and clinical outcomes, though supporting data is limited. Conclusion In professional football players, marrow stimulation is a viable treatment for the repair of small (<2 cm²), isolated cartilage injuries, though deterioration of mid- to long-term outcomes may hamper its widespread use. Multiple augmentation techniques have demonstrated the potential to generate a mechanically and biologically superior repair; however, more robust, high-level studies are needed to adequately assess efficacy.
... Such early loss of the subchondral bone induced by microfracture suggests that stimulation of new bone formation underlying the treated defects possibly occurs at later time points and, from a clinical perspective, highlights the importance of a protected weight-bearing within the first 6 weeks postoperatively when performing marrow stimulation in the tibiofemoral compartment (Gao et al., 2017;Steadman et al., 2001). Of special importance, sox9/hydrogel treatment led to a significantly higher BV/TV of the subchondral bone plate than the control treatment (P = 0.002), suggesting a preserving effect of the sox9/hydrogel on the subchondral bone plate. ...
... Non-operative therapies aim at managing symptoms using anti-inflammatory medication, viscosupplementation, bracing, orthotics, and activity modification (Buttgereit et al., 2015;Simon and Jackson, 2018). Drilling, abrasion, and microfracture of the subchondral bone provide surgical techniques to stimulate the intrinsic fibrocartilaginous repair process (Gao et al., 2018;Simon and Jackson, 2018;Steadman et al., 2001). At present, autologous chondrocyte implantation, periosteal transfer, and osteochondral autograft or allograft transplantation are commonly used clinical methods for the treatment of cartilage defects (Simon and Jackson, 2018). ...
... Microfracture is a relatively simple, minimally invasive, and costeffective technique to treat focal articular cartilage defects (Steadman et al., 2002;Steadman et al., 2001). However, microfracture has been shown to lead to fibrocartilage rather than normal hyaline cartilage regeneration (Dai et al., 2014;Steadman et al., 2002;Steadman et al., 2010;Truong et al., 2014;Xu et al., 2015). ...
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Background and aims Previous work has shown that oral losartan can enhance microfracture-mediated cartilage repair in a rabbit osteochondral defect injury model. In this study, we aimed to determine whether oral losartan would have a detrimental effect on articular cartilage and bone homeostasis in the uninjured sides. Methods New Zealand rabbits were divided into 4 groups including normal uninjured (Normal), contralateral uninjured side of osteochondral defect (Defect), osteochondral defect plus microfracture (Microfracture) and osteochondral defect plus microfracture and losartan oral administration (10 mg/kg/day) (Losartan). Rabbits underwent different surgeries and treatment and were sacrificed at 12 weeks. Both side of the normal group and uninjured side of treatment groups tibias were harvested for Micro-CT and histological analysis for cartilage and bone including H&E staining, Herovici's staining (bone and cartilage) Alcian blue and Safranin O staining (cartilage) as well as immunohistochemistry of losartan related signaling pathways molecules for both cartilage and bone. Results Our results showed losartan oral treatment at 10 mg/kg/day slightly increase Alcian blue positive matrix as well as decrease collagen type 3 in articular cartilage while having no significant effect on articular cartilage structure, cellularity, and other matrix. Losartan treatment also did not affect angiotensin receptor type 1 (AGTR1), angiotensin receptor type 2 (AGTR2) and phosphorylated transforming factor β1 activated kinase 1 (pTAK1) expression level and pattern in the articular cartilage. Furthermore, losartan treatment did not affect microarchitecture of normal cancellous bone and cortical bone of tibias compared to normal and other groups. Losartan treatment slightly increased osteocalcin positive osteoblasts on the surface of cancellous bone and did not affect bone matrix collagen type 1 content and did not change AGTR1, AGTR2 and pTAK1 signal molecule expression. Conclusion Oral losartan used as a microfracture augmentation therapeutic does not have significant effect on uninjured articular cartilage and bone based on our preclinical rabbit model. These results provided further evidence that the current regimen of using losartan as a microfracture augmentation therapeutic is safe with respect to bone and cartilage homeostasis and support clinical trials for its application in human cartilage repair.
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Focal cartilage defects may be associated with impaired quality of life in a similar manner to osteoarthritis. Patients can present with limited activity due to severe pain, recurrent effusions, dysfunction, and the eventual progression of joint degeneration.
Article
Objectives: In the aging population the knee is the joint most commonly causing impaired function and incapacity. While definite treatment by prosthetic replacement is often performed late, symptomatic knee cartilage lesions cause much suffering also in younger ages. Early intervention could therefore be instituted at an early stage to the benefit of both patients and society. Small, metal surface, resurfacing implants have been tested with promising results. A system, featuring patient specific implants and surgical instruments, shows good clinical results and favorable survival rates. This study aims to assess the cost-utility of this metal device compared with microfracture (MFX), being the standard procedure in Sweden. Methods: We constructed a simulation model in Excel. In the model, a cohort of 47-year-old patients (which is the mean age of patients treated with the metal implant) with symptomatic knee cartilage lesions received either MFX or metal implantation. Outcomes for the cohort were simulated over 40 years, like in a previously published model based on MFX, and sensitivity analyses (deterministic and probabilistic) of the results were undertaken. Data on transition probabilities, costs and quality of life was taken from clinical data, published literature and official price lists. Only direct medical costs were included. Results: Results from the analysis showed that the metal device is a cost-effective treatment strategy compared with MFX. The incremental cost effectiveness ratio (ICER) reached acceptable levels at ∼5 years postoperatively. Over the full-time horizon of 40 years, the metal device was cost saving with concomitant gains in quality-adjusted life-years (QALYs), translating to a dominant treatment strategy. Results were robust according to sensitivity analysis with the initial success rate up to 3 years for both metal and MFX having the largest impact. Conclusions: A metal implant may be a cost-effective treatment alternative for patients in their 40's when compared to MFX in a Swedish setting. Level of evidence: 5 [1].
Article
Significance: Cartilage tissue engineering is a promising strategy for effective curative therapies for treatment of osteoarthritis. However, tissue engineers depend predominantly on time-consuming, expensive, and destructive techniques as quality control to monitor the maturation of engineered cartilage. This practice can be impractical for large-scale biomanufacturing and prevents spatial and temporal monitoring of tissue growth, which is critical for the fabrication of clinically relevant-sized cartilage constructs. Nondestructive multimodal imaging techniques combining fluorescence lifetime imaging (FLIm) and optical coherence tomography (OCT) hold great potential to address this challenge. Aim: The feasibility of using multimodal FLIm-OCT for nondestructive, spatial, and temporal monitoring of self-assembled cartilage tissue maturation in a preclinical mouse model is investigated. Approach: Self-assembled cartilage constructs were developed for 4 weeks in vitro followed by 4 weeks of in vivo maturation in nude mice. Sterile and nondestructive in situ multispectral FLIm and OCT imaging were carried out at multiple time points ( t = 2 , 4, and 8 weeks) during tissue development. FLIm and 3D volumetric OCT images were reconstructed and used for the analysis of tissue biochemical homogeneity, morphology, and structural integrity. A biochemical homogeneity index was computed to characterize nonhomogeneous tissue growth at different time points. OCT images were validated against histology. Results: FLIm detects heterogenous extracellular matrix (ECM) growth of tissue-engineered cartilage. The outer edge of the tissue construct exhibited longer fluorescence lifetime in 375 to 410 and 450 to 485 nm spectral channels, indicating increase in collagen content. Significant ( p < 0.05 ) decrease of construct homogeneity index was observed between t = 2 weeks and t = 4 weeks. Both FLIm and OCT images revealed defects (voids) at the center of the tissue construct during in vitro culture ( t = 2 and 4 weeks). Cyst formation during in vivo culture was detected by OCT and confirmed with histology. Conclusions: The ability of multimodal FLIm-OCT to nondestructively monitor the heterogenous growth of engineered tissue constructs in situ is demonstrated. Spatial and temporal variation of construct ECM component was detected by FLIm. OCT reveals structural defects (voids and cysts). This multimodal approach has great potential to replace costly destructive tests in the manufacturing of tissue-engineered medical products, facilitating their clinical translation.
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Osteochondral lesions of the ankle joint are typically associated with a traumatic etiology and present with ankle pain and swelling. Conservative management yields unsatisfactory results because of the poor healing capacity of the articular cartilage. Smaller lesions (<100 mm2 or <10 mm) can be treated with less invasive procedures such as arthroscopic debridement, anterograde drilling, scaffold-based therapies, and augmentation with biological adjuvants. For patients with large lesions (>100 mm2 or >10 mm), cystic lesions, uncontained lesions, or patients who have failed prior bone marrow stimulation, management with autologous osteochondral transplantation is indicated.
Article
The current study was carried out to evaluate the effects of cartilage-decellularized extracellular matrix (ECM) on Poly (3-hydroxybutyrate) (PHB) electrospun scaffold for cartilage tissue engineering. In this study, PHB scaffolds with three different percentages of ECM (1%, 2%, and 3%) were fabricated. Mechanical, chemical, and physical properties of scaffolds along with their interactions with cells were assessed. Results showed that by adding of ECM to the scaffolds, the Physiomechanical properties of combined scaffolds were modified, compared to the pure PHB scaffold. In the other hand, the biological behavior was increased by increasing the ECM ratio to the PHB.
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Cartilage replacement materials exhibiting a set of demanding properties such as high water content, high mechanical stiffness, low friction, and excellent biocompatibility are quite difficult to achieve. Here, poly(p‐phenylene‐2,6‐benzobisoxazole) (PBO) nanofibers were combined with polyvinyl alcohol (PVA) to form a super‐strong structure with a performance that surpasses the vast majority of previously existing hydrogels. PVA‐PBO composites with water contents in the 59–76% range exhibited tensile and compressive moduli reaching 20.3 and 4.5 MPa, respectively, and a coefficient of friction below 0.08. Further, they were biocompatible and supported the viability of chondrocytes for one week, with significant improvements in cell adhesion, proliferation and differentiation compared to PVA. The new composites could be safely sterilized by steam heat or gamma radiation without compromising their integrity and overall performance. In addition, they showed potential to be used as delivery platforms of anti‐inflammatory drugs at the local level. These attractive features make PVA‐PBO composites highly competitive engineered materials with remarkable potential for use in the design of load‐bearing tissues. Complementary work has also revealed that these composites will be interesting alternatives in other industrial fields where high thermal and mechanical resistance are essential requirements, or which can take advantage of the pH responsiveness functionality. This article is protected by copyright. All rights reserved
Chapter
Once damaged, cartilage has limited healing capability. This has led to a huge body of research that aims to repair or regenerate this important tissue. Despite the progress made, significant hurdles still need to be overcome. This chapter highlights some of the progress made, while elaborating on areas that need further research. The concept of translation and the route to clinical translation must be kept in mind if some of the promising preclinical research is to make it to routine clinical application.
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Purpose To present mid-term patient reported outcomes and survivorship data of active-duty military patients undergoing microfracture for full-thickness cartilage defects of the glenoid. Methods All consecutive patients from January 2013 through December 2016 who underwent glenoid microfracture for full-thickness cartilage injuries with complete outcome scores were identified. Twenty patients met final inclusion criteria for the study, and all-were active-duty military at time of surgery. A separate subgroup analysis was performed to determine if dominant-shoulder involvement portends worse outcomes. Results Mean follow-up was 81.45±19.43 months (range 60-108). Of the 20 patients, 5 required a secondary surgical procedure within 5 years of their index procedure, with an average time to failure of 45.6±13.15 months. For the 15 patients who did not fail, there was a statistically significant increase in the mean American Shoulder and Elbow Surgeons (ASES) score (57.20 vs. 88.27, p < .0001) and Single Assessment Numeric Evaluation (SANE) (45.00 vs. 86.33, p < .0001). Mean pain decreased significantly as measured by the pain VAS (5.40 vs. 1.37, p < .0001). Range of motion in forward elevation, external rotation and internal rotation did not change significantly postoperatively (p = 0.4528, 0.4810 and 0.1919, respectively). Concomitant procedures did not predict changes in pain, ASES, or SANE scores. A majority of patients (13/20, 65%) were able to remain on unrestricted military active-duty service, but seven (35%) underwent medical discharge, including the five patients who had experienced treatment failure, plus two additional patients. Conclusion Glenoid microfracture can result in pain relief and symptomatic improvement for a select group of active-duty military patients, with 75% survivorship at five-years. Approximately one in three (35%) patients, however, were unable to remain on active-duty military service.
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This chapter starts with a brief description on the pathophysiological process after spinal cord injury and peripheral nerve injury and then focuses on the bio‐fabricated products that aid neural regeneration in central and peripheral nervous systems. Discussion on the mechanism of these products is also included. In the peripheral nervous system, the neural regeneration scaffolds improve the functional recovery after injury by rebalancing the microenvironment: (i) the overactive immune responses, (ii) the inefficient metabolic processes, (iii) the insufficient microcirculatory support, and (iv) the loss of bioelectrical signal conduction. In the central nervous system, the neural regeneration scaffolds (nanoparticles, electrospun fibers, and self‐assembled peptides) are reviewed, and the mechanism can be generally divided into three aspects: (i) to alleviate the inflammatory stress, (ii) to overcome the inhibitory effects, and (iii) to promote axonal regeneration. Finally, this chapter discusses the clinical application and evaluation of the neural regeneration scaffolds.
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Cartilage injury is still a major challenge that is waiting to be solved urgently in the field of orthopedic surgery because of the fact that articular cartilage has only a limited capacity for intrinsic healing. Without effective clinical intervention, cartilage injury could lead to the development of posttraumatic osteoarthritis (PTOA), which brings a tremendous economic and medical burden to the society. To address this issue, several strategies already applied in clinics to treat cartilage injury and defects. However, these strategies still need to evolve along with a better and broader understanding of cartilage injury. In this chapter, we first introduced some basic information of articular cartilage injury, and then we reviewed clinical strategies of cartilage injury and defects. Finally, we discussed some advanced techniques that possess great potential for treating cartilage injury in the future, such as bioactive materials for cartilage regeneration, gene editing tissue engineering, platelet‐rich plasma (PRP), etc. Some of these methods have progressed into preclinical trials in the treatment of cartilage injury, and more therapies in this field are still thriving to be developed.
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Articular cartilage (AC) has limited capacity for repair. The first attempt to repair cartilage using tissue engineering was reported in 1977. Since then, cell-based interventions have entered clinical practice in orthopaedics, and several tissue engineering approaches to repair cartilage are in the translational pipeline towards clinical application. Classically, these involve a scaffold, substrate or matrix to provide structure, and cells such as chondrocytes or mesenchymal stromal cells to generate the tissue. We will discuss the advantages and drawbacks of the use of various cell types, natural and synthetic scaffolds, multiphasic or gradient-based scaffolds, and self-organizing or self-assembling scaffold-free systems, for the engineering of cartilage constructs. Several challenges persist including achieving zonal tissue organization and integration with the surrounding tissue upon implantation. Approaches to improve cartilage thickness, organization and mechanical properties include mechanical stimulation, culture under hypoxic conditions, and stimulation with growth factors or other macromolecules. In addition, advanced technologies such as bioreactors, biosensors and 3D bioprinting are actively being explored. Understanding the underlying mechanisms of action of cell therapy and tissue engineering approaches will help improve and refine therapy development. Finally, we discuss recent studies of the intrinsic cellular and molecular mechanisms of cartilage repair that have identified novel signals and targets and are inspiring the development of molecular therapies to enhance the recruitment and cartilage reparative activity of joint-resident stem and progenitor cells. A one-fits-all solution is unrealistic, and identifying patients who will respond to a specific targeted treatment will be critical.
Article
Signals that recapitulate in vitro the conditions found in vivo, such as hypoxia or mechanical forces, contribute to the generation of tissue-engineered hyaline-like tissues. The cell regulatory processes behind hypoxic and mechanical stimuli rely on ion concentration; iron is required to degrade the hypoxia inducible factor 1a (HIF1α) under normoxia, whereas the initiation of mechanotransduction requires the cytoplasmic increase of calcium concentration. In this work, we propose that ion modulation can be used to improve the biomechanical properties of self-assembled neocartilage constructs derived from rejuvenated expanded minipig rib chondrocytes. The objectives of this work were 1) to determine the effects of iron sequestration on self-assembled neocartilage constructs using two doses of the iron chelator deferoxamine (DFO), and 2) to evaluate the performance of the combined treatment of DFO and ionomycin, a calcium ionophore that triggers cytoplasmic calcium accumulation. This study employed a two-phase approach. In Phase I, constructs treated with a high dose of DFO (100 µM) exhibited an 87% increase in pyridinoline crosslinks, a 57% increase in the Young's modulus, and a 112% increase in the ultimate tensile strength (UTS) of the neotissue. In Phase II, the combined use of both ion modulators resulted in 150% and 176% significant increases in the Young's modulus and UTS of neocartilage constructs, respectively; for the first time, neocartilage constructs achieved a Young's modulus of 11.76±3.29 MPa and UTS of 4.20±1.24 MPa. The results of this work provide evidence that ion modulation can be employed to improve the biomechanical properties in engineered neotissues. Statement of Significance : The translation of tissue-engineered products requires the development of strategies capable of producing biomimetic neotissues in a replicable, controllable, and cost-effective manner. Among other functions, Fe²⁺ and Ca²⁺ are involved in the control of the hypoxic response and mechanotransduction, respectively. Both stimuli, hypoxia and mechanical forces, are known to favor chondrogenesis. This study utilized ion modulators to improve the mechanical properties self-assembled neocartilage constructs derived from expanded and rejuvenated costal chondrocytes via Fe²⁺ sequestration and Ca²⁺ influx, alone or in combination. The results indicate that ion modulation induced tissue maturation and a significant improvement of the mechanical properties, and holds potential as a tool to mitigate the need for bioreactors and engineer hyaline-like tissues.
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The surgical management of focal cartilage lesions of the knee continues to be a challenging problem for the orthopedic surgeon. Among the many available options, microfracture is still considered the first-line treatment for symptomatic small chondral lesions. Nevertheless, this procedure results in the formation of a fibrocartilaginous repair tissue with inferior biomechanical properties compared to normal hyaline cartilage. Thus, despite positive short-term results, long-term results are inconsistent and often less satisfactory, with loss of improvement over time. Over the years, therefore, an increasing number of strategies for the augmentation of microfracture have been introduced to improve repair tissue characteristics and reduce long-term deterioration. On one side, some researchers investigated the effect of intra-articular augmentation of injectable products, including growth factors, hyaluronic acid, blood concentrates, and minimally manipulated mesenchymal stromal cells (MSCs), to enhance the concentration of growth factors and MSCs released from the subchondral bone marrow. On the other side, some researchers proposed the use of biodegradable biomaterials (scaffolds) as an augmentation to bone marrow stimulation to provide a temporary support which is capable of increasing the mechanical stability of the early clot, thus allowing for better growth of cells migrated from the subchondral bone marrow. Both augmentation techniques showed promising clinical results compared with microfracture alone, and they also seemed to improve the quality of the repair tissue of microfracture, producing a more hyaline-like repair capable of durable, long-term functional improvement; but there are no high-level studies or long-term results that confirm the potential of microfracture plus approaches.
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Injury to articular cartilage can result from femoroacetabular impingement (FAI). Early damage may manifest as peripheral cartilage delamination from subchondral bone. This is demonstrated during hip arthroscopy by the “wave” sign. Studies have shown that within this damaged cartilage there are viable chondrocytes. It is therefore reasonable to consider surgical methods, which preserve rather than excise these areas of chondral damage. Since the early twentieth century, fibrin has been used in surgery because of its hemostatic and adhesive properties. Consequently, a technique has been developed which uses a combination of the microfracture principals with fibrin glue to adhere delaminated cartilage back to subchondral bone. Fibrin has been shown not only to adhere to cartilage but also to encourage migration and proliferation of chondrocytes to areas of damaged cartilage. This encourages a repopulation of chondrocytes and healthy hyaline cartilage. Studies have shown this method to be at least comparable, if not superior, to traditional cartilage sacrificing techniques such as chondroplasty and microfracture alone.
Article
Bone marrow stimulation (BMS) is indicated for patients who have symptomatic osteochondral lesions of the talus (OLT). Despite differences in ankle biomechanics and cartilage morphology between men and women, there is scant evidence examining whether these differences affect surgical outcomes. The purpose of this study was to compare the outcomes in men and women following BMS for OLTs. A retrospective analysis comparing female and male patients treated with BMS for OLT between 2007 and 2015 was performed. Clinical outcomes were evaluated using the Foot and Ankle Outcome Scores (FAOS) and Short-Form 12 (SF-12). Magnetic resonance imaging (MRI) at final follow-up was evaluated with the modified magnetic resonance observation of cartilage repair tissue (MOCART) score. Thirty-one females and 38 males were included. In female patients, the mean FAOS pain score improved from 60±16 preoperatively to 84±8.9 at 1-2 year follow-up (p<0.01), and then decreased to 80±13 at final follow-up at 3-4 years. In male patients, the mean FAOS pain score improved from 65±17 preoperatively to 83±9.2 at 1-2 year follow-up (p<0.01), and then decreased to 76±14.6 at final follow-up at 3-4 years. Lateral lesions were more common in male patients. Medial lesions were more common in female patients. The outcomes following BMS in both female and male patients were good with no significant differences at short term follow-up. FAOS scores in male patients were more likely to decrease after 1-2 years post-surgery, implying a possibly faster decline than in female patients.
Article
Cartilage regeneration is a priority in medicine for the treatment of osteoarthritis and isolated cartilage defects. Several molecules with potential for cartilage regeneration are under investigation. Unfortunately, in vitro chondrogenesis assays do not always predict the stability of the newly formed cartilage in vivo. Therefore, there is a need for a stringent, quantifiable assay to assess in vivo the capacity of molecules to promote the stable formation of cartilage that is resistant to calcification and endochondral bone formation. We developed an ectopic cartilage formation assay (ECFA) that enables one to assess the capacity of bioactive molecules to support cartilage formation in vivo using cartilage organoids. The ECFA predicted good clinical outcomes when used as a quality control for efficacy of chondrocyte preparations before implantation in patients with cartilage defects. In this assay, articular chondrocytes from human donors or animals are injected either intramuscularly or subcutaneously in nude mice. As early as 2 weeks later, cartilage organoids can be retrieved. The size of the implants and their degree of differentiation can be assessed by histomorphometry, immunostainings of molecular markers and real-time PCR. Mineralization can be assessed by micro-computed tomography or by staining. The effects of molecules on cartilage formation can be tested following the systemic administration of the molecule in mice previously injected with chondrocytes, or after co-injection of chondrocytes with cell lines overexpressing and secreting the protein of interest. Here we describe the ECFA procedure, including steps for harvesting human and bovine articular cartilage, isolating primary chondrocytes, preparing overexpression cell lines, injecting the cells intramuscularly and retrieving the implants. This assay can be performed by technicians and researchers with appropriate animal training within 3 weeks.
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Tissue engineering (TE) combines cells and biomaterials to treat orthopedic pathologies. Maturation of de novo tissue is highly dependent on local mechanical environments. Mechanical stimulation influences stem cell differentiation, however, the role of various mechanical loads remains unclear. While bioreactors simplify the complexity of the human body, the potential combination of mechanical loads that can be applied make it difficult to assess how different factors interact. Human bone marrow-derived mesenchymal stromal cells were seeded within a fibrin-polyurethane scaffold and exposed to joint-mimicking motion. We applied a full factorial design of experiment to investigate the effect that the interaction between different mechanical loading parameters has on biological markers. Additionally, we employed planned contrasts to analyze differences between loading protocols and a linear mixed model with donor as random effect. Our approach enables screening of multiple mechanical loading combinations and identification of significant interactions that could not have been studied using classical mechanobiology studies. This is useful to screen the effect of various loading protocols and could also be used for TE experiments with small sample sizes and further combinatorial medication studies.
Article
Objective Articular cartilage defects in the hip joint pose a challenge to obtain a successful outcome. They often lead to significant pain and disability. The aim of this literature review was to report the best available evidence on the various treatment options for hip cartilage defects. Material and methods A comprehensive literature search was performed on PubMed from its inception to October 2021 using the following search strategy: ((hip) and (cartilage or chondral) and (repair or regeneration or restoration or implantation or chondroplasty or chondrogenic)). Two reviewers (KHSK, MG) independently reviewed titles and abstracts to identify articles for the final analysis. Articles were included if they were original research studies (randomised control trials, cohort studies, case-control studies, or comparative studies) on treatment of hip cartilage defects reporting on a minimum of 5 patients in humans. A total of 1172 articles were identified on the literature search. Following a thorough selection proceed 35 articles were included in the final analysis to synthesise the evidence. Results Debridement, microfracture, autologous chondocyte implanatation (ACI) and matrix-induced ACI (MACI) are shown to have good short-to medium-term results. Injectable ACI and MACI have been developed to enable these procedures to be performed via arthroscopic surgery to reduce the post-operative morbidity associated with surgery with promising early results. Large cartilage defects which involved the sub-chodaral bone may need the use of osteochondral grafts either autograft or allograft in case of larger defects. Newer biological solutions have been developed to potentially deliver a single-stage procedure for hip cartilage injuries but longer-term results are still awaited. Conclusion Accurate identification of the extent of the injury help stratify the defect and plan appropriate treatment. Several surgical techniques have shown good short-to medium-term outcomes on ACI, AMIC, mosaicplasty and microfracture. Recent advances made enabled the use of injectable MACI and bioscaffolds which show promising results but in the short term. However, one needs to be mindful of the techniques which can be used in their surgical setting with the available resources. In order to thoroughly evaluate the benefits of the different surgical techniques for hip cartilage defects, large scale prospective multi-centre studies are necessary Perhaps inclusion of such procedure in registries may yield results in large numbers.
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】 Articular cartilage (AC)cannot repair itself due to the lack of blood vessels, nerves and lymph, To some extent, exogenous cell-based treatment strategies can regenerate articular cartilage, however, there were some risks such as long surgical interval, limited donor availability, easy cell dedifferentiation in vitro and pathogen transmission. When cartilage is damaged, many kinds of stem cells/progenitor cells (SCPCs)in adult knee joints will be mobilized and migrated to damaged area and participate in regeneration repair. Therefore, based on recruitment endogenous SCPCs, the in-situ AC regeneration strategy has become a research hotspot, which fully utilizes the body's self-repair potential and avoids the disadvantages of exogenous cell strategy. The characteristics and migration pathway of different SCPCs in the knee joint and its role in the repair of cartilage injury were introduced. At the same time, progress of endogenous AC regeneration and repair strategies were mainly focused, in order to attract more researchers to participate in this promising research field.
Article
Objective To provide an evidence-based overview of the different surgical procedures in osteoarthritis (OA). Method This narrative review reports on surgical therapies (1) for severe, end stage OA and (2) of surgical options aiming to possibly reduce OA development earlier in the course of the disease. Results Surgical practice guidelines provide evidence-based recommendations to assist in the clinical decision-making. Total joint arthroplasty represents the only valuable, established surgical option for severe, end stage OA. For hip and knee OA, it is by far the most common surgical procedure and provides considerable pain relief, functional restoration, and improved quality of life. Surgical therapy aiming to postpone OA essentially addresses extra- or intraarticular pre-osteoarthritic deformities, defined as congenital or acquired disturbances of the joint structure that adversely affect its function. Approaches in this category include osteotomies and different cartilage repair procedures such as osteochondral autograft and allograft transfer, marrow stimulation techniques, and autologous chondrocyte implantation. However, they are not only less commonly performed than arthroplasty, but the scientific clinical evidence in favour of this type of surgery to reduce the long-term risk of developing OA is considerably reduced. Conclusion Total knee and hip arthroplasty are two of the most successful procedures in all of medicine. As the progression of this insidious disease is often asymptomatic and slow, it is imperative to judge reparative procedures at their potential to reduce OA development at long-term, besides their primary clinical outcomes. Evidence-based guidelines provide a valuable tool for high-quality surgical decision making in OA.
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This user-friendly, pragmatic book discusses the normal and pathological conditions of the appendicular skeleton, with a focus on the preservation of joint function, providing a detailed overview of strategies for both common and complex joint preservation. The first section covers basic topics, ranging from joints homeostasis and biomechanics, to genetics, bio-orthopedics, tissue engineering and 3D bioprinting. The following sections are each dedicated to a specific joint – its functional anatomy, pathologic conditions, diagnostics and treatment. This book is of interest to orthopedists and sports medicine specialists treating common and complex injuries of the joints.
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The rehabilitation of chondral injuries and degenerative knees is challenging. Setting short- and long-term goals enables the athlete to cope with the psychology of injury while facilitating a return to sport. Rehabilitation must be gradual, progressive, and goal oriented for each individual. Protocols must include range of motion, flexibility exercises, strength training, and cross training. Compliance with all aspects off the program is important and the athlete must have direct communication with the therapist via telephone conversation and/or personal appointments. Carefully guided rehabilitation affords athletes the means necessary to regain functional use of the limb while promoting dynamic unloading of injured articular cartilage.
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Knowledge of the structure and function of articular cartilage is important when considering rehabilitation following surgical procedures for articular cartilage lesions of the knee. Articular cartilage is avascular and derives its nutrition primarily from synovial fluid, resulting in a limited potential for regeneration. Basic science evidence has demonstrated that compressive loading may have a positive impact on articular cartilage healing; however, excessive shear loading may be detrimental. Rehabilitation following surgical procedures for articular cartilage lesions should include controlled range of motion exercises. Exercises to enhance muscle function must be done in a manner which minimizes shear loading of the joint surfaces in the area of the lesion. A period of protected weight bearing is often necessary and should be followed by progressive loading of the joint. This article will: 1) provide a brief review of the structure and function of articular cartilage lesions as it relates to rehabilitation; 2) describe common surgical procedures to address articular cartilage lesions; and 3) provide guidelines for rehabilitation following surgical management of articular cartilage lesions.
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Disorders of articular cartilage represent some of the most common and debilitating diseases encountered in orthopaedic practice. Understanding the normal functioning of articular cartilage is a prerequisite to understanding its pathologic processes. The mechanical properties of articular cartilage arise from the complex structure and interactions of its biochemical constituents: mostly water, electrolytes, and a solid matrix composed primarily of collagen and proteoglycan. The viscoelastic properties of cartilage, due primarily to fluid flow through the solid matrix, can explain much of the deformational responses observed under many loading conditions. Degenerative processes can often be explained by a breakdown of the normal load-bearing capacity of cartilage which arises from the mechanics of this fluid flow. Several factors which may lead to such a breakdown include direct trauma to the cartilage, obesity, immobilization, and excessive repetitive loading of the cartilage. Sports activity, without traumatic injury, does not appear to be a risk factor for the development of osteoarthritis in the normal joint; however, such activity may be harmful to an abnormal joint.
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Impact and torsional joint loading can injure articular cartilage, causing pain, joint dysfunction and effusions, and, in some instances, progressive joint degeneration. Differences in the type of injury and the repair response distinguish three classes of articular surface injuries: 1) damage to the joint surface that leaves the articular surface intact but causes internal chondral damage and may cause subchondral bone injury, 2) mechanical disruption of the articular surface limited to articular cartilage, and 3) mechanical disruption of articular cartilage and subchondral bone. A variety of treatments has the potential to improve healing of articular surfaces, including perforation of subchondral bone, altered joint loading, periosteal and perichondrial grafts, cell transplantation, growth factors, and artificial matrices. Selection of treatment for a patient with an articular cartilage injury should be guided by an understanding of the type of injury, the potential for healing, and the effects of treatment on joint surface restoration.
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The objective of this study was to elucidate how cryotherapy after anterior cruciate ligament reconstruction affects intraarticular temperature and clinical results. A prospective and randomized study was performed on 21 knees of 21 patients. The ligament reconstruction was performed by single-incision arthroscopy using autogenous hamstring tendon. On completion of the surgery, thermosensors were implanted in the suprapatellar pouch and the intracondylar notch, and the intraarticular temperature was monitored while the joint was cooled. Cooling was performed in one group at 5 degrees C (N = 7) and in another at 10 degrees C (N = 7), for 48 hours. A control group (N = 7) did not undergo cryotherapy. The cooled groups showed three temperature phases: a low-temperature phase immediately after the ligament reconstruction, followed by a temperature-rising phase and a thermostatic phase. The control group had no low-temperature phase and immediately entered a thermostatic phase. During the low-temperature phase in the treated groups, the temperature of the suprapatellar pouch and of the intercondylar notch were significantly lower than the body temperature. The pain score and the number of times an analgesic had to be administered were both significantly lower in the 10 degrees C group than in the control group. Blood loss was significantly less in the 5 degrees C group than in the control group.