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    The Use of Bone Marrow Concentrate in the Treatment of Full-Thickness Chondral Defects. Apostolakos John M,Lazaro Lionel,Williams Riley J HSS journal : the musculoskeletal journal of Hospital for Special Surgery This article is a critical analysis of a study, "Minimally Manipulated Bone Marrow Concentrate Compared with Microfracture Treatment of Full-Thickness Chondral Defects: A One-Year Study in an Equine Model," by Chu et al. (. 100(2):138-146, 2018). The investigation compared two interventions in the management of full-thickness chondral defects in an equine model: autologous bone marrow concentrate without concomitant microfracture treatment versus microfracture treatment alone. This review analyzes the methodology and results of their investigation and examines how their findings may influence the continued development of therapeutic options for full-thickness cartilage injuries. The study utilized in vitro analysis, arthroscopic assessment, magnetic resonance imaging (MRI) evaluation, and histological analysis to compare the treatments and their influence on the quality of cartilage repair. Although Chu et al. reported similar results between groups, their findings offer insight into the role of arthroscopy, MRI, and histology in the evaluation of repair quality. We compare their findings to those of similar investigations, highlighting the limited therapeutic options and variable clinical outcomes related to the treatment of full-thickness articular cartilage defects. 10.1007/s11420-018-9647-z
    [Research progress of surgical treatment for anterior shoulder dislocation and combined injuries]. Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery OBJECTIVE:To summarize the research progress of surgical treatment for anterior shoulder dislocation and combined injuries. METHODS:The related literature was reviewed, and the surgical treatment options for the anterior shoulder dislocation and its combined injuries were summarized. RESULTS:Anterior shoulder dislocation can combine with anteroinferior capsular ligament complex injury (Bankart injury), bony Bankart defect, and Hill-Sachs lesion. For Bankart and bony Bankart injuries, arthroscopic repair or coracoid osteotomy combined with bony graft reconstruction can be performed. For Hill-Sachs lesion, conservative treatment, soft tissue repair, or bony reconstruction should be selected based on the extent of the bone defect. For bipolar injury, the Bankart repair, Remplissage, or arthroplasty should be selected based on the extent of the glenoid defect. CONCLUSION:With the development of arthroscopy and the improvement of the surgical concept, there is a complete set of surgical options for various injuries of the anterior shoulder dislocation. When choosing a surgical procedure, the patient's specific injury and age, exercise level, and other relating factors should be comprehensively assessed in order to achieve the best results. 10.7507/1002-1892.201901021
    Autologous costal chondral transplantation and costa-derived chondrocyte implantation: emerging surgical techniques. Gao Youshui,Gao Junjie,Li Hengyuan,Du Dajiang,Jin Dongxu,Zheng Minghao,Zhang Changqing Therapeutic advances in musculoskeletal disease It is a great challenge to cure symptomatic lesions and considerable defects of hyaline cartilage due to its complex structure and poor self-repair capacity. If left untreated, unmatured degeneration will cause significant complications. Surgical intervention to repair cartilage may prevent progressive joint degeneration. A series of surgical techniques, including biological augmentation, microfracture and bone marrow stimulation, autologous chondrocyte implantation (ACI), and allogenic and autogenic chondral/osteochondral transplantation, have been used for various indications. However, the limited repairing capacity and the potential pitfalls of these techniques cannot be ignored. Increasing evidence has shown promising outcomes from ACI and cartilage transplantation. Nevertheless, the morbidity of autologous donor sites and limited resource of allogeneic bone have considerably restricted the wide application of these surgical techniques. Costal cartilage, which preserves permanent chondrocytes and the natural osteochondral junction, is an ideal candidate for the restoration of cartilage defects. Several and studies have shown good performance of costal cartilage transplantation. Although costal cartilage is a classic donor in plastic and cosmetic surgery, it is rarely used in skeletal cartilage restoration. In this review, we introduce the fundamental properties of costal cartilage and summarize costa-derived chondrocyte implantation and costal chondral/osteochondral transplantation. We will also discuss the pitfalls and pearls of costal cartilage transplantation. Costal chondral/osteochondral transplantation and costa-based chondrocytotherapy might be up-and-coming surgical techniques for recalcitrant cartilage lesions. 10.1177/1759720X19877131
    3D bioprinting in orthopedics translational research. Zheng XuanQi,Huang JinFeng,Lin JiaLiang,Yang DeJun,Xu TianZhen,Chen Dong,Zan Xingjie,Wu AiMin Journal of biomaterials science. Polymer edition The repair of critical-size bone defect remains a challenge for orthopedic surgeons. With the advent of an aging society and their accompanying chronic diseases, it is becoming more difficult to treat bone defects, especially large segmental bone defects that are caused by trauma, tumors, infections, and congenital malformations. New materials and technologies need to be developed to address these conditions. 3D bioprinting is a novel technology that bridges the biomaterial and living cells and is an important method in tissue engineering projects. 3D bioprinting has the advantages of replacing or repairing damaged tissue and organs. The progress in material science and 3D printing devices make 3D bioprinting a technology which can be used to create various scaffolds with a large range of advanced material and cell types. However, in regard to the widespread use of bioprinting, biosafety, immunogenicity and rising costs are rising to be concerned. This article reviews the developments and applications of 3D bioprinting and highlights newly applied techniques and materials and the recent achievements in the orthopedic field. This paper also briefly reviews the difference between the methods of 3D bioprinting. The challenges are also elaborated with the aim to research materials, manufacture scaffolds, promote vascularization and maintain cell viability. 10.1080/09205063.2019.1623989
    Impact of developmental origin, niche mechanics and oxygen availability on osteogenic differentiation capacity of mesenchymal stem/stromal cells. Bryniarska Natalia,Kubiak Andrzej,Łabędź-Masłowska Anna,Zuba-Surma Ewa Acta biochimica Polonica Mesenchymal Stem/Stromal Cells (MSCs) have been widely considered as a promising source of cells for tissue regeneration. Among other stem cells, they are characterized by a high osteogenic potential. Intensive studies in this field had shown that even if basic osteogenic differentiation is relatively simple, its clinical application requires more sophisticated approaches to prepare effective and safe cell therapy products. The aim of this review is to underline biological, physical and chemical factors which play a crucial role in osteogenic differentiation of MSCs. Existence of two distinct mechanisms of ossification (intramembranous and endochondral) indicate that choosing a proper source of MSCs may be critical for successful regeneration of a particular bone type. In this context, Dental Pulp Stem Cells representing a group of MSCs and originating from neural crest ( a structure responsible for development of cranial bones) are considered as the most promising for skull bone defect repair. Factors which facilitate osteogenic differentiation of MSCs include changes in forces exerted on cells during development. Thus, culturing of cells in hydrogels or on biocompatible three-dimensional scaffolds improves osteogenic differentiation of MSCs by both, the mechanotransductive and chemical impact on cells. Moreover, atmospheric oxygen concentration routinely used for cell cultures in vitro does not correspond to lower oxygen concentration present in stem cell niches. A decrease in oxygen concentration allows to create more physiological cell culture conditions, mimicking the ones in stem cell niches, which promote the MSCs stemness. Altogether, factors discussed in this review provide exciting opportunities to boost MSCs propagation and osteogenic differentiation which is crucial for successful clinical applications. 10.18388/abp.2019_2893
    Cartilage Restoration: Microfracture and Osteochondral Autograft Transplantation. Redondo Michael L,Beer Adam J,Yanke Adam B The journal of knee surgery The treatment of patellofemoral cartilage defects presents several distinct challenges when compared with cartilage restoration techniques used for other compartments of the knee due to the unique anatomy and distribution of forces. The etiologies of patellofemoral articular cartilage lesions include acute traumatic instability injuries, such as dislocation and subluxation, osteochondritis dissecans, and chronic degenerative changes. Regardless of the etiology, untreated patellofemoral cartilage lesions can contribute to activity-limiting anterior knee pain. The goal of patellofemoral cartilage restoration procedures is to impart symptomatic relief and improve quality of life by repairing the articular cartilage surface and any comorbid malalignment or maltracking.Microfracture and osteochondral autograft transplantation (OAT) are two cartilage restoration procedures to consider when treating full-thickness patellofemoral chondral defects. Considered by some experts to be the gold standard therapy, microfracture is one of the most common procedures used for cartilage restoration. The technique involves the perforation of the subchondral bone plate for the release of marrow elements, filling the defect with a fibrocartilage clot repair. Though less commonly used, OAT allows defect replacement with native hyaline cartilage via autologous transplantation from a non-weight bearing area. The purpose of this article is to discuss the indication, technical considerations, and outcomes of microfracture and OAT when used for treating chondral lesions of the patellofemoral joint. 10.1055/s-0037-1618592
    Articular Cartilage Repair of the Knee in Children and Adolescents. Salzmann Gian M,Niemeyer Philipp,Hochrein Alfred,Stoddart Martin J,Angele Peter Orthopaedic journal of sports medicine Articular cartilage predominantly serves a biomechanical function, which begins in utero and further develops during growth and locomotion. With regard to its 2-tissue structure (chondrocytes and matrix), the regenerative potential of hyaline cartilage defects is limited. Children and adolescents are increasingly suffering from articular cartilage and osteochondral deficiencies. Traumatic incidents often result in damage to the joint surfaces, while repetitive microtrauma may cause osteochondritis dissecans. When compared with their adult counterparts, children and adolescents have a greater capacity to regenerate articular cartilage defects. Even so, articular cartilage injuries in this age group may predispose them to premature osteoarthritis. Consequently, surgery is indicated in young patients when conservative measures fail. The operative techniques for articular cartilage injuries traditionally performed in adults may be performed in children, although an individualized approach must be tailored according to patient and defect characteristics. Clear guidelines for defect dimension-associated techniques have not been reported. Knee joint dimensions must be considered and correlated with respect to the cartilage defect size. Particular attention must be given to the subchondral bone, which is frequently affected in children and adolescents. Articular cartilage repair techniques appear to be safe in this cohort of patients, and no differences in complication rates have been reported when compared with adult patients. Particularly, autologous chondrocyte implantation has good biological potential, especially for large-diameter joint surface defects. 10.1177/2325967118760190
    [Current advances on surgical treatment for knee articular cartilage injuries]. Xin Long,Zhang Chun,Xu Wei-Xing,Zhong Fu-Hua,Fan Shun-Wu,Wang Zhen-Bin Zhongguo gu shang = China journal of orthopaedics and traumatology Chondral injuries are short of self-healing ability and need to surgical repair after articular cartilage injury. Conventional treatment includes debridement and drainage under arthroscope, micro-fracture, osteochondral autograft transplantation (OATS), mosaiplasty and osteochondral allografts (OCA), autologous chondrocyte implantation (ACI). Debridement and drainage could remove pain factor, and has advantages of simple operation, wide clinical application and early clinical effect. Micro-fracture and osteochondral autograft transplantation is suitable for small area of cartilage repair, while the further effect showed that fibrous cartilage permeated by drill could decrease postoperative clinical effect. Osteochondral autograft transplantation has better advantages for reconstruction complete of wear-bearing joint. Autologous chondrocyte implantation and allogeneic cartilage transplantation are suitable for large area of cartilage defect, postoperative survival of allogeneic cartilage transplantation is effected by local rejection reaction and decrease further clinical effect. Cartilage tissue engineering technology could improve repair quality of autologous chondrocyte implantation, and make repair tissue close to transparent cartilage, but has limit to combined subchondral bone plate, reactive bone edema, bone loss and bad axis of lower limb. New technology is applied to cartilage injury, and has advantages of less trauma, simple operation, rapid recover, good clinical effect and less cost;and could be main method for treat cartilage injury with surgical repair technology. How to improve repair quality with compression resistance and abrasive resistance are expected to be solved. 10.3969/j.issn.1003-0034.2018.03.019
    [Research progress of rehabilitation after autologous chondrocyte implantation on knee]. Lin Yipeng,Li Tao,Xiong Yan,Li Jian,Fu Weili Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery Objective:To summarize the research progress of rehabilitation after autologous chondrocyte implantation (ACI). Methods:The literature related to basic science and clinical practice about rehabilitation after ACI in recent years was searched, selected, and analyzed. Results:Based on the included literature, the progress of the graft maturation consists of proliferation phase (0-6 weeks), transition phase (6-12 weeks), remodeling phase (12-26 weeks), and maturation phase (26 weeks-2 years). To achieve early protection, stimulate the maturation, and promote the graft-bone integrity, rehabilitation protocol ought to be based on the biomechanical properties at different phases. Weight-bearing program, range of motion (ROM), and options or facilities of exercise are importance when considering a rehabilitation program. Conclusion:It has been proved that the patients need a program with an increasingly progressive weight-bearing and ROM in principles of rehabilitation after ACI. Specific facilities can be taken at a certain phase. Evidences extracted in the present work are rather low and the high-quality and controlled trials still need to improve the rehabilitation protocol. 10.7507/1002-1892.201801034
    Adaptive Materials Based on Iron Oxide Nanoparticles for Bone Regeneration. Li Yan,Ye Dewen,Li Mingxi,Ma Ming,Gu Ning Chemphyschem : a European journal of chemical physics and physical chemistry The paper provides a brief overview of the use of iron oxide nanoparticles (IONPs) in the areas of bone regenerative medicine. Reconstruction of bone defects caused by trauma, non-union, and bone tumor excision, still faces many challenges despite the intense investigations and advancement in bone-tissue engineering and bone regeneration over the past decades. IONPs have promising prospects in this field due to their controlled responsive characteristics in specific external magnetic fields and have been of great interest during the last few years. This Minireview aims to summarize the relevant progress and describes the following five aspects: (i) The general introduction of IONPs, with a focus on the magnetic properties as the base of application; (ii) using IONPs as tools to study and control stem cells for better treatment efficacy in stem-cell-based bone defect repair; (iii) the use of IONPs and their complexes in the delivery of therapeutic agents, including chemical drug molecules, growth factors, and genetic materials, to promote osteogenesis-related cell function and differentiation, healthy bone tissue growth, and functional reconstruction; (iv) magneto-mechanical actuation in the regulation of cells distribution, mechano-transduction membrane receptors activation, and mechanosensitive signaling pathways regulation, and (v) fabrication, characteristics, and in vitro and in vivo osteogenic effects of magnetic composite bone scaffolds. Ongoing prospects are also discussed. 10.1002/cphc.201701294
    Demineralized Bone Matrix Carriers and their Clinical Applications: An Overview. Zhang Hao,Yang Li,Yang Xiong-Gang,Wang Feng,Feng Jiang-Tao,Hua Kun-Chi,Li Qi,Hu Yong-Cheng Orthopaedic surgery Reconstruction of massive bone defects is challenging for orthopaedic clinicians, especially in cases of severe trauma and resection of tumors in various locales. Autologous iliac crest bone graft (ICBG) is the "gold standard" for bone grafting. However, the limited availability and complications at donor sites resulted in seeking other options like allografts and bone graft substitutes. Demineralized bone matrix (DBM) is a form of allograft using acidic solution to remove mineral components, while leaving much of the proteinaceous components native to bone, with small amounts of calcium-based solids, inorganic phosphates, and some trace cell debris. It is an osteoconductive and osteoinductive biomaterial and is approved as a medical device for use in bone defects and spinal fusion. To pack consistently into the defect sites and stay firmly in the filling parts, DBM products have various forms combined with biocompatible viscous carriers, including sponges, strips, injectable putty, paste, and paste infused with chips. The present review aims to summarize the properties of various kind of viscous carriers and their clinical use combined with DBM in commercially available products. Given DBM'mercially available products. Given DBM;s long clinical track record and commercial accessibility in standard forms, opportunities to further develop and validate DBM as a versatile bone biomaterial in orthopaedic repair and regenerative medicine contexts are attractive. 10.1111/os.12509
    Nanostructured Surface Modification to Bone Implants for Bone Regeneration. Wang Quan,Huang Yixing,Qian Zhiyong Journal of biomedical nanotechnology Bone defect repair is a complex process of bone regeneration. Bone substitute implanted at the bone defect sites act as three-dimensional scaffolds that guide and promote bone regeneration. The function of orthopedic implants is often limited by complicating factors such as insufficient integration into host tissue, inflammatory reactions, and infection. Biological behaviors of immune cells and osteogenesis-related cells on these bone biomaterials are largely determined by the surface properties. The advances in nanofabrication technology have help us fabricated a range of nanostructured surface with controlled physicochemical properties to modulate the behaviors of osteogenesis-related cells and immune cells, thus affecting bone integration and local immune reaction. In this review, we summary the development of nanostructured surface modification to bone implants with controlled physicochemical properties, including roughness, wettability, surface charge and topography. In particular, we focus on the effect of nanotopographies on cell recruitment and cellular adhesion, osteogenic differentiation, mineralization and osseointegration, antibacterial activities, and modulation of immune response. 10.1166/jbn.2018.2516
    The Potential for Synovium-derived Stem Cells in Cartilage Repair. Kubosch Eva Johanna,Lang Gernot,Furst David,Kubosch David,Izadpanah Kaywan,Rolauffs Bernd,Sudkamp Norbert P,Schmal Hagen Current stem cell research & therapy BACKGROUND:Articular cartilage defects often result in pain, loss of function and finally osteoarthritis. Developing cell-based therapies for cartilage repair is a major goal of orthopaedic research. Autologous chondrocyte implantation is currently the gold standard cell-based surgical procedure for the treatment of large, isolated, full thickness cartilage defects. Several disadvantages such as the need for two surgical procedures or hypertrophic regenerative cartilage, underline the need for alternative cell sources. OBJECTIVE:Mesenchymal stem cells, particularly synovium-derived mesenchymal stem cells, represent a promising cell source. Synovium-derived mesenchymal stem cells have attracted considerable attention since they display great chondrogenic potential and less hypertrophic differentiation than mesenchymal stem cells derived from bone marrow. The aim of this review was to summarize the current knowledge on the chondrogenic potential for synovial stem cells in regard to cartilage repair purposes. RESULTS:A literature search was carried out identifying 260 articles in the databases up to January 2017. Several in vitro and initial animal in vivo studies of cartilage repair using synovia stem cell application showed encouraging results. Since synvoium-derived stem cells are located in the direct vicinity of cartilage and cartilage lesions these cells might even contribute to natural cartilage regeneration. The only one published human in vivo study with 10 patients revealed good results concerning postoperative outcome, MRI, and histologic features after a two-stage implantation of synovial stem cells into an isolated cartilage defect of the femoral condyle. CONCLUSION:Synovium-derived stem cells possess great chondrogenic potential and showed encouraging results for cartilage repair purposes. Furthermore, synovial stem cells play an important role in joint homeostasis and possibly in natural cartilage repair. Further studies are needed to elucidate the interplay of synovial stem cells and chondrocytes, and the promising role of synovium-derived stem cells in cartilage tissue engineering. 10.2174/1574888X12666171002111026
    The Therapeutic Potential of MicroRNAs as Orthobiologics for Skeletal Fractures. Hadjiargyrou Michael,Komatsu David E Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research The repair of a fractured bone is critical to the well-being of humans. Failure of the repair process to proceed normally can lead to complicated fractures, exemplified by either a delay in union or a complete nonunion. Both of these conditions lead to pain, the possibility of additional surgery, and impairment of life quality. Additionally, work productivity decreases, income is reduced, and treatment costs increase, resulting in financial hardship. Thus, developing effective treatments for these difficult fractures or even accelerating the normal physiological repair process is warranted. Accumulating evidence shows that microRNAs (miRNAs), small noncoding RNAs, can serve as key regulatory molecules of fracture repair. In this review, a brief description of the fracture repair process and miRNA biogenesis is presented, as well as a summary of our current knowledge of the involvement of miRNAs in physiological fracture repair, osteoporotic fractures, and bone defect healing. Further, miRNA polymorphisms associated with fractures, miRNA presence in exosomes, and miRNAs as potential therapeutic orthobiologics are also discussed. This is a timely review as several miRNA-based therapeutics have recently entered clinical trials for nonskeletal applications and thus it is incumbent upon bone researchers to explore whether miRNAs can become the next class of orthobiologics for the treatment of skeletal fractures. 10.1002/jbmr.3708
    From skeletal development to the creation of pluripotent stem cell-derived bone-forming progenitors. Tam Wai Long,Luyten Frank P,Roberts Scott J Philosophical transactions of the Royal Society of London. Series B, Biological sciences Bone has many functions. It is responsible for protecting the underlying soft organs, it allows locomotion, houses the bone marrow and stores minerals such as calcium and phosphate. Upon damage, bone tissue can efficiently repair itself. However, healing is hampered if the defect exceeds a critical size and/or is in compromised conditions. The isolation or generation of bone-forming progenitors has applicability to skeletal repair and may be used in tissue engineering approaches. Traditionally, bone engineering uses osteochondrogenic stem cells, which are combined with scaffold materials and growth factors. Despite promising preclinical data, limited translation towards the clinic has been observed to date. There may be several reasons for this including the lack of robust cell populations with favourable proliferative and differentiation capacities. However, perhaps the most pertinent reason is the failure to produce an implant that can replicate the developmental programme that is observed during skeletal repair. Pluripotent stem cells (PSCs) can potentially offer a solution for bone tissue engineering by providing unlimited cell sources at various stages of differentiation. In this review, we summarize key embryonic signalling pathways in bone formation coupled with PSC differentiation strategies for the derivation of bone-forming progenitors.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'. 10.1098/rstb.2017.0218
    Meta-Analysis and Evidence Base for the Efficacy of Autologous Bone Marrow Mesenchymal Stem Cells in Knee Cartilage Repair: Methodological Guidelines and Quality Assessment. Awad Mohamed E,Hussein Khaled A,Helwa Inas,Abdelsamid Mohamed F,Aguilar-Perez Alexandra,Mohsen Ibrahim,Hunter Monte,Hamrick Mark W,Isales Carlos M,Elsalanty Mohammed,Hill William D,Fulzele Sadanand Stem cells international The aim of this study is to review all the published clinical trials on autologous bone marrow mesenchymal stem cells (BM-MSCs) in the repair of cartilage lesions of the knee. We performed a comprehensive search in three electronic databases: PubMed, Medline via Ovid, and Web of Science. A systematic review was conducted according to the guidelines of PRISMA protocol and the Cochrane Handbook for Systematic Reviews of Interventions. The modified Coleman methodology score was used to assess the quality of the included studies. Meta-analysis was conducted to estimate the effect size for Pain and function change after receiving BM-MSCs. Thirty-three studies-including 724 patients of mean age 44.2 years-were eligible. 50.7% of the included patients received cultured BM-MSCs for knee cartilage repair. There was improvement in the MINORS quality score over time with a positive correlation with the publication year. Meta-analysis indicated better improvement and statistical significance in the Visual Analog Scale for Pain, IKDC Function, Tegner Activity Scale, and Lysholm Knee Score after administration of noncultured BM-MSCs when compared to evaluation before the treatment. Meanwhile, there was a clear methodological defect in most studies with an average modified Coleman methodology score (MCMS) of 55. BM-MSCs revealed a clinically relevant improvement in pain, function, and histological regeneration. 10.1155/2019/3826054
    Mimicking the 3D biology of osteochondral tissue with microfluidic-based solutions: breakthroughs towards boosting drug testing and discovery. Carvalho Mariana R,Reis Rui Luís,Oliveira Joaquim Miguel Drug discovery today The development of tissue-engineering (TE) solutions for osteochondral (OC) regeneration has been slowed by technical hurdles related to the recapitulation of their complex and hierarchical architecture. OC defects refer to damage of both the articular cartilage and the underlying subchondral bone. To repair an OC tissue defect, the complexity of the bone and cartilage must be considered. To help achieve this, microfluidics is converging with TE approaches to provide new treatment possibilities. Microfluidics uses precise micrometer-to-millimeter-scale fluid flows to achieve high-resolution and spatial and/or temporal control of the cell microenvironment, providing powerful tools for cell culturing. Herein, we overview the progress of microfluidics for developing 3D in vitro models of OC tissue, with a focus on cancer bone metastasis. 10.1016/j.drudis.2018.01.008
    Three-dimensional (3D) printed scaffold and material selection for bone repair. Zhang Lei,Yang Guojing,Johnson Blake N,Jia Xiaofeng Acta biomaterialia Critical-sized bone defect repair remains a substantial challenge in clinical settings and requires bone grafts or bone substitute materials. However, existing biomaterials often do not meet the clinical requirements of structural support, osteoinductive property, and controllable biodegradability. To treat large-scale bone defects, the development of three-dimensional (3D) porous scaffolds has received considerable focus within bone engineering. A variety of biomaterials and manufacturing methods, including 3D printing, have emerged to fabricate patient-specific bioactive scaffolds that possess controlled micro-architectures for bridging bone defects in complex configurations. During the last decade, with the development of the 3D printing industry, a large number of tissue-engineered scaffolds have been created for preclinical and clinical applications using novel materials and innovative technologies. Thus, this review provides a brief overview of current progress in existing biomaterials and tissue engineering scaffolds prepared by 3D printing technologies, with an emphasis on the material selection, scaffold design optimization, and their preclinical and clinical applications in the repair of critical-sized bone defects. Furthermore, it will elaborate on the current limitations and potential future prospects of 3D printing technology. STATEMENT OF SIGNIFICANCE: 3D printing has emerged as a critical fabrication process for bone engineering due to its ability to control bulk geometry and internal structure of tissue scaffolds. The advancement of bioprinting methods and compatible ink materials for bone engineering have been a major focus to develop optimal 3D scaffolds for bone defect repair. Achieving a successful balance of cellular function, cellular viability, and mechanical integrity under load-bearing conditions is critical. Hybridization of natural and synthetic polymer-based materials is a promising approach to create novel tissue engineered scaffolds that combines the advantages of both materials and meets various requirements, including biological activity, mechanical strength, easy fabrication and controllable degradation. 3D printing is linked to the future of bone grafts to create on-demand patient-specific scaffolds. 10.1016/j.actbio.2018.11.039
    High Voltage Electric Burn Repair of the Forehead by Reverse Flow Temporalis Muscle Flap. Coruh Atilla Journal of burn care & research : official publication of the American Burn Association Repairing soft tissue defects of the forehead which exposes the bare bone is a dilemma with few reconstructive techniques for plastic surgeons. Forehead is an important aesthetic unit of the face which is covered with the glabrous skin. Due to the relative lack of similar mobile tissue locally, reconstruction of large soft tissue defects of the forehead region by local flaps is demanding. Temporalis muscle flap does not reach to the midline of the forehead region because of the insufficient length of the deep temporal vascular system. During the transfer of the muscle, only a small volume and size of the muscle can reach to the defect, remaining most of the muscle bulk in the pedicle and a relatively limited arc of rotation, thus a small volume of usable tissue at the distal portion of the flap. We successfully used reverse flow temporalis muscle flap for the purpose of eliminating the above-mentioned disadvantage of temporalis muscle flap in a 23-year-old male patient who sustained a high-voltage electrical burn resulting 12 × 8 cm left forehead defect exposing the bare bone. 10.1093/jbcr/irz024
    [Research progress on induced membrane technique for the treatment of segmental bone defect]. Jin Zhi-Chao,Cai Qun-Bin,Zeng Zhi-Kui,Li Ding,Li Yue,Huang Pei-Zhen,Zheng Xiao-Hui Zhongguo gu shang = China journal of orthopaedics and traumatology Treatment of large bone defects caused by trauma, osteomyelitis, and tumors has been a major challenge in clinical. In the past, there have been many ways to repair and reconstruct the large bone defects. However, there is a long period of treatment, high technical requirement and complications such as ununion. After Masquelet reported the induced membrane technology in 2000, the technique was widely used in treatment of trauma, osteomyelitis, and large bone defects caused by tumors. It has been obtained good results. It has the advantages of short course, high healing rate, easy operation and easy to master. The induced membrane has unique structural characteristics and biological characteristics. There are many kinds of osteogenic factors that are included in the membrane, such as vascular endothelial growth factor, and morphogenetic protein-2, transforming growth factor-β1, etc. These osteogenic factors contribute to accelerate bone healing. With the development of induced membrane technology. The technology of Reamer Irrigator Aspirator technology, engineering tissue technology and internal fixation is used in clinic.It can provide bone source, promote bone defect reconstruction, improve long-term limb function and reduce complications.This paper retrospectively summarizes the experimental research and clinical progress of Masquelet technique in the treatment of large bone defects. 10.3969/j.issn.1003-0034.2018.05.018
    Osteochondral Tissue Engineering: Translational Research and Turning Research into Products. Spencer Victoria,Illescas Erica,Maltes Lorenzo,Kim Hyun,Sathe Vinayak,Nukavarapu Syam Advances in experimental medicine and biology Osteochondral (OC) defect repair is a significant clinical challenge. Osteoarthritis results in articular cartilage/subchondral bone tissue degeneration and tissue loss, which in the long run results in cartilage/ostecochondral defect formation. OC defects are commonly approached with autografts and allografts, and both these options have found limitations. Alternatively, tissue engineered strategies with biodegradable scaffolds with and without cells and growth factors have been developed. In order to approach regeneration of complex tissues such as osteochondral, advanced tissue engineered grafts including biphasic, triphasic, and gradient configurations are considered. The graft design is motivated to promote cartilage and bone layer formation with an interdigitating transitional zone (i.e., bone-cartilage interface). Some of the engineered OC grafts with autologous cells have shown promise for OC defect repair and a few of them have advanced into clinical trials. This chapter presents synthetic osteochondral designs and the progress that has been made in terms of the clinical translation. 10.1007/978-3-319-76711-6_17
    Lateral Toe Pulp Flap Used in Reconstruction of Distal Dorsal Toe Defect: Case Report and Review of the Literature. Cheng Li-Fu,Lee Jiunn-Tat,Wu Meng-Si Annals of plastic surgery BACKGROUND:When the distal dorsal part of the great toe is injured, especially with exposure of a tendon, bone, or joint, applying a free or local flap is difficult because of the lack of locally available tissue for reconstruction. Management of the distal dorsal part of a great toe soft tissue defect can be challenging for plastic surgeons. PATIENT AND METHOD:An 18-year-old woman presented with an injury to the dorsal aspect of her right great toe caused by a cobra bite. After fasciotomy, the wound showed exposure of the extensor hallucis longus tendon. After demarcation and infection control, the wound was reconstructed using a lateral toe pulp flap of approximately 3.5 × 1.0 cm. The flap was transposed to the defect, and the donor site was closed primarily. Toe pulp flaps are mainly used to reconstruct finger pulp defects and are useful because they provide a glabrous skin flap suitable for resurfacing fingertip injuries. A lateral toe pulp flap uses a homodigital adjacent skin flap, which is transposed to cover the soft tissue defect. Using a quick and straightforward procedure, we designed this flap to reconstruct a distal dorsal defect of the great toe, with minimal morbidity at the donor site. RESULTS:The flap initially showed mild congestion but survived completely. CONCLUSIONS:Applying a lateral toe pulp flap is a quick, simple, and reliable 1-stage procedure. It may be an effective option in reconstructing distal dorsal defects of the great toe. 10.1097/SAP.0000000000001703
    [Advances in the research and application of orbital blowout fracture repair material]. Yu J H,Xu Q H,Wang Y H,Liao H F [Zhonghua yan ke za zhi] Chinese journal of ophthalmology Orbital blowout fractures can easily lead to defects of the orbital wall. In order to restore the continuity of the bone wall and avoid a series of clinical symptoms caused by orbital contents herniation or incarceration, the site of the defect should be reconstructed. The effect of reconstruction depends on the choice of surgical plan and repair material. The typical materials for bone wall defect repair include bone sheet, high density porous polyethylene, titanium mesh, absorbable polymer, bioactive ceramics and tissue engineering bone. This paper reviews the research findings and application of material for repairing of orbital blowout fracture. . 10.3760/cma.j.issn.0412-4081.2019.11.019
    Recent Progress in the Construction of Functional Artificial Bone by Cytokine-Controlled Strategies. Bao Xiao-Gang,Shi Meng-Chao,Hou Chun-Lin,Xu Guo-Hua Chinese medical journal OBJECTIVE:Combining artificial scaffolds with stimulatory factors to reconstruct lost bone tissues is one of the hottest research directions. The purpose of this review was to conduct a retrospective survey on the latest reports on artificial bone fabrication with functional cytokines. DATA SOURCES:The status of related scientific research from the year 2005 to 2018 was analyzed through the mode of literature retrieval in PubMed and VIP Database. The retrieval words are as follows: "bone tissue engineering," "angiogenesis," "cytokines," "osteogenesis," "biomimetic bone marrow," "sol-gel," "delivery system," and the corresponding Chinese words. STUDY SELECTION:After reading through the title and abstract for early screening, the full text of relevant studies was evaluated and those not related with this review had been ruled out. RESULTS:According to the literature retrospective survey, there were three key points for the successful construction of functional artificial bones: (1) the continuous supply of relatively low concentration of cytokines during the required period; (2) the delivery of two or more cytokines essential to the process and ensure the relatively spatial independence to reduce the unnecessary interference; and (3) supporting the early-stage angiogenesis and late-stage osteogenesis, respectively, regulating and balancing the crosslinking of both to avoid the surface ossification that would probably block the osteogenesis inside. CONCLUSIONS:The synergistic effect of both angiogenic factors and osteogenic factors applied in bone regeneration is a key point in the combined functional artificial bone. Through analysis, comparison, and summary of the current strategies, we proposed that the most promising one is to mimic the natural bone marrow function to facilitate the regeneration process and ensure the efficient repair of large weight-bearing bone defect. 10.4103/0366-6999.244105
    [Research progress of surgical treatment for lateral malleolus defect]. Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery OBJECTIVE:To review the research progress of the surgical treatment for lateral malleolus defect. METHODS:The related literature about surgical treatment and effectiveness of lateral malleolus defect at home and abroad was reviewed, summarized, and analysed. RESULTS:Lateral malleolus defects are often caused by severe trauma or wide resection of fibular neoplasms. Although the incidence is not high, the defects are difficult to handle. These bony defects should be reconstructed to prevent an abnormal gait induced by ankle instability and avoid the occurrence of traumatic arthritis. Various repair methods have been developed, including bone transplantation, fibula lengthening, and ankle arthrodesis. CONCLUSION:There are various surgical methods to repair the defect of lateral malleolus, but each has its own advantages and disadvantages. In order to achieve the best results, the surgeon should choose the appropriate operation according to his own level, the patient's specific injury, and age. 10.7507/1002-1892.201902047
    Chitosan in Surface Modification for Bone Tissue Engineering Applications. Abinaya Balakrishnan,Prasith Tandiakkal Prakash,Ashwin Badrinath,Viji Chandran Syamala,Selvamurugan Nagarajan Biotechnology journal Traditional methods of bone defect repair include autografts, allografts, surgical reconstruction, and metal implants that have several disadvantages such as donor site morbidity, rejection, risk of disease transmission, and repetitive surgery. Biomaterial-based bone reconstructions can, therefore, be an efficient alternative due to the inherent properties of the materials. Chitosan (CS), the deacetylated form of chitin, is a biopolymer having a wide array of applicability in regenerative tissue applications owing to its biocompatible, in vitro degradative and bioresorbable nature. Extensive studies are being carried out using CS to augment the properties of the already existing methods and to also improve the applicability of CS-based biocomposites in bone tissue repair. In this review, the suitability of CS as a surface modifier has been discussed in detail for the already existing implants, surface modifications of CS-based natural biocomposites for bone tissue regeneration, and the wide range of techniques that can introduce these modifications. CS, being a natural polymer, possesses advantageous properties including surface modifier that makes it a suitable candidate for bone regeneration, and further research to investigate its osteogenic potential in vivo along with the molecular and signaling mechanisms involved in bone regeneration can aid in expanding its applicability in clinical trials. 10.1002/biot.201900171
    Scaffolds for the repair of bone defects in clinical studies: a systematic review. Zeng Jian-Hua,Liu Shi-Wei,Xiong Long,Qiu Peng,Ding Ling-Hua,Xiong Shi-Lang,Li Jing-Tang,Liao Xin-Gen,Tang Zhi-Ming Journal of orthopaedic surgery and research BACKGROUND:This systematic review aims to summarize the clinical studies on the use of scaffolds in the repair of bony defects. METHODS:The relevant articles were searched through PubMed database. The following keywords and search terms were used: "scaffolds," "patient," "clinic," "bone repair," "bone regeneration," "repairing bone defect," "repair of bone," "osteanagenesis," "osteanaphysis," and "osteoanagenesis." The articles were screened according to inclusion and exclusion criteria, performed by two reviewers. RESULTS:A total of 373 articles were obtained using PubMed database. After screening, 20 articles were identified as relevant for the purpose of this systematic review. We collected the data of biological scaffolds and synthetic scaffolds. There are eight clinical studies of biological scaffolds included collagen, gelatin, and cellular scaffolds for bone healing. In addition, 12 clinical studies of synthetic scaffolds on HAp, TCP, bonelike, and their complex scaffolds for repairing bone defects were involved in this systematic review. CONCLUSIONS:There are a lot of clinical evidences showed that application of scaffolds had a good ability to facilitate bone repair and osteogenesis. However, the ideal and reliable guidelines are insufficiently applied and the number and quality of studies in this field remain to be improved. 10.1186/s13018-018-0724-2
    Four-dimensional bioprinting: Current developments and applications in bone tissue engineering. Wan Zhuqing,Zhang Ping,Liu Yunsong,Lv Longwei,Zhou Yongsheng Acta biomaterialia Four-dimensional (4D) bioprinting, in which the concept of time is integrated with three-dimensional (3D) bioprinting as the fourth dimension, has currently emerged as the next-generation solution of tissue engineering as it presents the possibility of constructing complex, functional structures. 4D bioprinting can be used to fabricate dynamic 3D-patterned biological architectures that will change their shapes under various stimuli by employing stimuli-responsive materials. The functional transformation and maturation of printed cell-laden constructs over time are also regarded as 4D bioprinting, providing unprecedented potential for bone tissue engineering. The shape memory properties of printed structures cater to the need for personalized bone defect repair and the functional maturation procedures promote the osteogenic differentiation of stem cells. In this review, we introduce the application of different stimuli-responsive biomaterials in tissue engineering and a series of 4D bioprinting strategies based on functional transformation of printed structures. Furthermore, we discuss the application of 4D bioprinting in bone tissue engineering, as well as the current challenges and future perspectives. STATEMENTS OF SIGNIFICANCE: In this review, we have demonstrated the 4D bioprinting technologies, which integrate the concept of time within the traditional 3D bioprinting technology as the fourth dimension and facilitate the fabrications of complex, functional biological architectures. These 4D bioprinting structures could go through shape or functional transformation over time via using different stimuli-responsive biomaterials and a series of 4D bioprinting strategies. Moreover, by summarizing potential applications of 4D bioprinting in the field of bone tissue engineering, these emerging technologies could fulfill unaddressed medical requirements. The further discussions about future challenges and perspectives will give us more inspirations about widespread applications of this emerging technology for tissue engineering in biomedical field. 10.1016/j.actbio.2019.10.038
    Management of Bone Defects in Orthopedic Trauma. Gage Mark,Liporace Frank,Egol Kenneth,McLaurin Toni Bulletin of the Hospital for Joint Disease (2013) Treatment of traumatic bone defects is dictated by a multitude of clinical factors including the defect size, patient comorbidities, soft tissue condition, and the possibility of infection present in the defect. With a variety of treatment strategies described, it is critical to choose the approach that will maximize outcomes in addressing this difficult problem. When addressing small-scale defects, bone grafting is the primary treatment. For large-scale defects, there are two major options to consider: induced membrane technique and distraction osteogenesis. Choosing between these two techniques should be based on the associated soft tissue injury, the local vascularity, and the possibility of residual infection. This review will focus on the current management principles and strategies in the treatment of bone defects after orthopedic trauma and the existing literature to support each of these treatment options.
    Local delivery of adenosine receptor agonists to promote bone regeneration and defect healing. Lopez Christopher D,Bekisz Jonathan M,Corciulo Carmen,Mediero Aranzazu,Coelho Paulo G,Witek Lukasz,Flores Roberto L,Cronstein Bruce N Advanced drug delivery reviews Adenosine receptor activation has been investigated as a potential therapeutic approach to heal bone. Bone has enhanced regenerative potential when influenced by either direct or indirect adenosine receptor agonism. As investigators continue to elucidate how adenosine influences bone cell homeostasis at the cellular and molecular levels, a small but growing body of literature has reported successful in vivo applications of adenosine delivery. This review summarizes the role adenosine receptor ligation plays in osteoblast and osteoclast biology and remodeling/regeneration. It also reports on all the modalities described in the literature at this point for delivery of adenosine through in vivo models for bone healing and regeneration. 10.1016/j.addr.2018.06.010
    Calvarial Suture-Derived Stem Cells and Their Contribution to Cranial Bone Repair. Doro Daniel H,Grigoriadis Agamemnon E,Liu Karen J Frontiers in physiology In addition to the natural turnover during life, the bones in the skeleton possess the ability to self-repair in response to injury or disease-related bone loss. Based on studies of bone defect models, both processes are largely supported by resident stem cells. In the long bones, the source of skeletal stem cells has been widely investigated over the years, where the major stem cell population is thought to reside in the perivascular niche of the bone marrow. In contrast, we have very limited knowledge about the stem cells contributing to the repair of calvarial bones. In fact, until recently, the presence of specific stem cells in adult craniofacial bones was uncertain. These flat bones are mainly formed via intramembranous rather than endochondral ossification and thus contain minimal bone marrow space. It has been previously proposed that the overlying periosteum and underlying dura mater provide osteoprogenitors for calvarial bone repair. Nonetheless, recent studies have identified a major stem cell population within the suture mesenchyme with multiple differentiation abilities and intrinsic reparative potential. Here we provide an updated review of calvarial stem cells and potential mechanisms of regulation in the context of skull injury repair. 10.3389/fphys.2017.00956
    Sphingosine 1-phosphate (S1P) signalling: Role in bone biology and potential therapeutic target for bone repair. Sartawi Ziad,Schipani Ernestina,Ryan Katie B,Waeber Christian Pharmacological research The lipid mediator sphingosine 1-phosphate (S1P) affects cellular functions in most systems. Interest in its therapeutic potential has increased following the discovery of its G protein-coupled receptors and the recent availability of agents that can be safely administered in humans. Although the role of S1P in bone biology has been the focus of much less research than its role in the nervous, cardiovascular and immune systems, it is becoming clear that this lipid influences many of the functions, pathways and cell types that play a key role in bone maintenance and repair. Indeed, S1P is implicated in many osteogenesis-related processes including stem cell recruitment and subsequent differentiation, differentiation and survival of osteoblasts, and coupling of the latter cell type with osteoclasts. In addition, S1P's role in promoting angiogenesis is well-established. The pleiotropic effects of S1P on bone and blood vessels have significant potential therapeutic implications, as current therapeutic approaches for critical bone defects show significant limitations. Because of the complex effects of S1P on bone, the pharmacology of S1P-like agents and their physico-chemical properties, it is likely that therapeutic delivery of S1P agents will offer significant advantages compared to larger molecular weight factors. Hence, it is important to explore novel methods of utilizing S1P agents therapeutically, and improve our understanding of how S1P and its receptors modulate bone physiology and repair. 10.1016/j.phrs.2017.08.013
    Efficacy of platelet concentrates in bone healing: A systematic review on animal studies - Part B: Large-size animal models. Marcazzan Sabrina,Taschieri Silvio,Weinstein Roberto Lodovico,Del Fabbro Massimo Platelets In the presence of large bone defects, delayed bone union, or nonunion and fractures, bone reconstruction may be necessary. Different strategies have been employed to enhance bone healing among which the use of autologous platelet concentrates (APCs). Due to the high content of platelets and platelet-derived bioactive molecules (e.g., growth factors, antimicrobial peptides), they are promising candidates to enhance bone healing. However, both preclinical and clinical studies produced contrasting results, mainly due to a high heterogeneity in study design, objectives, techniques adopted, and outcomes assessed. The aim of the present systematic review was to evaluate the efficacy of APCs in animal models of bone regeneration, considering the possible factors that might affect the outcome. An electronic search was performed on MEDLINE and Scopus databases. Comparative animal studies with a minimum follow up of 2 weeks, at least five subjects per group and using APCs for regeneration of bone defects were included. Articles underwent risk of bias assessment and quality evaluation. Fifty studies performed on six animal species (rat, rabbit, dog, sheep, goat, mini-pig) were included. The present part of the review considers studies performed on small ruminants, dogs, and mini-pigs (14 articles). The majority of the studies were considered at low risk of bias. In general, APCs' adjunct positively affected bone regeneration. Animal species, platelet and growth factors concentration, type of bone defect and of platelet concentrate used seemed to influence their efficacy in bone healing. However, sound conclusions were not drawn since too few studies for each large-size animal model were included. In addition, characterization of APCs' content was performed only in a few studies. Further studies with a standardized protocol including characterization of the final products will provide useful information for translating the results to clinical application of APCs in bone surgery. 10.1080/09537104.2017.1384537
    Advanced Therapy Medicinal Products: A Guide for Bone Marrow-derived MSC Application in Bone and Cartilage Tissue Engineering. Confalonieri Davide,Schwab Andrea,Walles Heike,Ehlicke Franziska Tissue engineering. Part B, Reviews Millions of people worldwide suffer from trauma- or age-related orthopedic diseases such as osteoarthritis, osteoporosis, or cancer. Tissue Engineering (TE) and Regenerative Medicine are multidisciplinary fields focusing on the development of artificial organs, biomimetic engineered tissues, and cells to restore or maintain tissue and organ function. While allogenic and future autologous transplantations are nowadays the gold standards for both cartilage and bone defect repair, they are both subject to important limitations such as availability of healthy tissue, donor site morbidity, and graft rejection. Tissue engineered bone and cartilage products represent a promising and alternative approach with the potential to overcome these limitations. Since the development of Advanced Therapy Medicinal Products (ATMPs) such as TE products requires the knowledge of diverse regulation and an extensive communication with the national/international authorities, the aim of this review is therefore to summarize the state of the art on the clinical applications of human bone marrow-derived stromal cells for cartilage and bone TE. In addition, this review provides an overview of the European legislation to facilitate the development and commercialization of new ATMPs. 10.1089/ten.TEB.2017.0305
    Functionalized cell-free scaffolds for bone defect repair inspired by self-healing of bone fractures: A review and new perspectives. Li Li,Lu Hongwei,Zhao Yulan,Luo Jiangming,Yang Li,Liu Wanqian,He Qingyi Materials science & engineering. C, Materials for biological applications Studies have demonstrated that scaffolds, a component of bone tissue engineering, play an indispensable role in bone repair. However, these scaffolds involving ex-vivo cultivated cells seeded have disadvantages in clinical practice, such as limited autologous cells, time-consuming cell expansion procedures, low survival rate and immune-rejection issues. To overcome these disadvantages, recent focus has been placed on the design of functionalized cell-free scaffolds, instead of cell-seeded scaffolds, that can reduplicate the natural self-healing events of bone fractures, such as inflammation, cell recruitment, vascularization, and osteogenic differentiation. New approaches and applications in tissue engineering and regenerative medicine continue to drive the development of functionalized cell-free scaffolds for bone repair. In this review, the self-healing processes were highlighted, and approaches for the functionalization were summarized. Also, ongoing efforts and breakthroughs in the field of functionalization for bone defect repair were discussed. Finally, a brief summery and new perspectives for functionalization strategies were presented to provide guidelines for further efforts in the design of bioinspired cell-free scaffolds. 10.1016/j.msec.2019.01.075