Cardiovascular diseases cause significant morbidity and mortality worldwide. Engineered cardiac organoids are being developed and used to replicate cardiac tissues supporting cardiac morphogenesis and development. These organoids have applications in drug screening, cardiac disease models and regenerative medicine. Therefore, a thorough understanding of cardiac organoids and a comprehensive overview of their development are essential for cardiac tissue engineering. This review summarises different types of cardiac organoids used to explore cardiac function, including those based on co–culture, aggregation, scaffolds, and geometries. The self–assembly of monolayers, multilayers and aggravated cardiomyocytes forms biofunctional cell aggregates in cardiac organoids, elucidating the formation mechanism of scaffold–free cardiac organoids. In contrast, scaffolds such as decellularised extracellular matrices, three–dimensional hydrogels and bioprinting techniques provide a supportive framework for cardiac organoids, playing a crucial role in cardiac development. Different geometries are engineered to create cardiac organoids, facilitating the investigation of intrinsic communication between cardiac organoids and biomechanical pathways. Additionally, this review emphasises the relationship between cardiac organoids and the cardiac system, and evaluates their clinical applications. This review aims to provide valuable insights into the study of three–dimensional cardiac organoids and their clinical potential.
Stem cell–derived spinal cord organoids (SCOs) have revolutionised the study of spinal cord development and disease mechanisms, offering a three-dimensional model that recapitulates the complexity of native tissue. This review synthesises recent advancements in SCO technology, highlighting their role in modelling spinal cord morphogenesis and their application in neurodegenerative disease research. We discuss the methodological breakthroughs in inducing regional specification and cellular diversity within SCOs, which have enhanced their predictive ability for drug screening and their relevance in mimicking pathological conditions such as neurodegenerative diseases and neuromuscular disorders. Despite these strides, challenges in achieving vascularisation and mature neuronal integration persist. The future of SCOs lies in addressing these limitations, potentially leading to transformative impactions in regenerative medicine and therapeutic development.
The convergence of organoid technology and artificial intelligence (AI) is poised to revolutionise oral healthcare. Organoids – three–dimensional structures derived from human tissues – offer invaluable insights into the complex biology of diseases, allowing researchers to effectively study disease mechanisms and test therapeutic interventions in environments that closely mimic in vivo conditions. In this review, we first present the historical development of organoids and delve into the current types of oral organoids, focusing on their use in disease models, regeneration and microbiome intervention. We then compare single–source and multi–lineage oral organoids and assess the latest progress in bioprinted, vascularised and neural–integrated organoids. In the next part of the review, we highlight significant advancements in AI, emphasising how AI algorithms may potentially promote organoid development for early disease detection and diagnosis, personalised treatment, disease prediction and drug screening. However, our main finding is the identification of remaining challenges, such as data integration and the critical need for rigorous validation of AI algorithms to ensure their clinical reliability. Our main viewpoint is that current AI–enabled oral organoids are still limited in applications but, as we look to the future, we offer insights into the potential transformation of AI–integrated oral organoids in oral disease diagnosis, oral microbial interactions and drug discoveries. By synthesising these components, this review aims to provide a comprehensive perspective on the current state and future implications of AI–enabled oral organoids, emphasising their role in advancing oral healthcare and improving patient outcomes.
The skeletal system, composed of bones, muscles, joints, ligaments, and tendons, serves as the foundation for maintaining human posture, mobility, and overall biomechanical functionality. However, with ageing, chronic overuse, and acute injuries, conditions such as osteoarthritis, intervertebral disc degeneration, muscle atrophy, and ligament or tendon tears have become increasingly prevalent and pose serious clinical challenges. These disorders not only result in pain, functional loss, and a marked reduction in patients’ quality of life but also impose substantial social and economic burdens. Current treatment modalities, including surgical intervention, pharmacotherapy, and physical rehabilitation, often do not effectively restore the functionality of damaged tissues and are associated with high recurrence rates and long–term complications, highlighting significant limitations in their efficacy. Thus, there is a strong demand to develop novel and more effective therapeutic and reparative strategies. Organoid technology, as a three–dimensional micro–tissue model, can replicate the structural and functional properties of native tissues in vitro, providing a novel platform for in–depth studies of disease mechanisms, optimisation of drug screening, and promotion of tissue regeneration. In recent years, substantial advancements have been made in the research of bone, muscle, and joint organoids, demonstrating their broad application potential in personalised and regenerative medicine. Nonetheless, a comprehensive review of current research on skeletal organoids is still lacking. Therefore, this article aims to present an overview of the definition and technological foundation of organoids, systematically summarise the progress in the construction and application of skeletal organoids, and explore future opportunities and challenges in this field, offering valuable insights and references for researchers.
Cardiovascular diseases are a leading cause of death worldwide, and effective treatment for cardiac disease has been a research focal point. Although the development of new drugs and strategies has never ceased, the existing drug development process relies primarily on rodent models such as mice, which have significant shortcomings in predicting human responses. Therefore, human–based in vitro cardiac tissue models are considered to simulate physiological and functional characteristics more effectively, advancing disease treatment and drug development. The microfluidic device simulates the physiological functions and pathological states of the human heart by culture, thereby reducing the need for animal experimentation and enhancing the efficiency and accuracy of the research. The basic framework of cardiac chips typically includes multiple functional units, effectively simulating different parts of the heart and allowing the observation of cardiac cell growth and responses under various drug treatments and disease conditions. To date, cardiac chips have demonstrated significant application value in drug development, toxicology testing, and the construction of cardiac disease models; they not only accelerate drug screening but also provide a new research platform for understanding cardiac diseases. In the future, with advancements in functionality, integration, and personalised medicine, cardiac chips will further simulate multiorgan systems, becoming vital tools for disease modelling and precision medicine. Here, we emphasised the development history of cardiac organ chips, highlighted the material selection and construction strategy of cardiac organ chip electrodes and hydrogels, introduced the current application scenarios of cardiac organ chips, and discussed the development opportunities and prospects for their of biomedical applications.
Bone and cartilage tissues are essential for movement and structure, yet diseases like osteoarthritis affect millions. Traditional therapies have limitations, necessitating innovative approaches. Organoid technology, leveraging stem cells’ regenerative potential, offers a novel platform for disease modelling and therapy. This review focuses on advancements in bone/cartilage organoid technology, highlighting the role of stem cells, biomaterials, and external factors in organoid development. We discuss the implications of these organoids for regenerative medicine, disease research, and personalised treatment strategies, presenting organoids as a promising avenue for enhancing cartilage repair and bone regeneration. Bone/cartilage organoids will play a greater role in the treatment of bone/cartilage diseases in the future, and promote the progress of biological tissue engineering.
Bone defects are a prevalent category of skeletal tissue disorders in clinical practice, with a range of pathogenic factors and frequently suboptimal clinical treatment effects. In bone regeneration of bone defects, the bone regeneration microenvironment—composed of physiological, chemical, and physical components—is the core element that dynamically coordinates to promote bone regeneration. In recent years, medical biomaterials with bioactivity and functional tunability have been widely researched upon and applied in the fields of tissue replacement/regeneration, and remodelling of organ structure and function. The biomaterial treatment system based on the comprehensive regulation strategy of bone regeneration microenvironment is expected to solve the clinical problem of bone defect. Hydrogel microspheres (HMS) possess a highly specific surface area and porosity, an easily adjustable physical structure, and high encapsulation efficiency for drugs and stem cells. They can serve as highly efficient carriers for bioactive factors, gene agents, and stem cells, showing potential advantages in the comprehensive regulation of bone regeneration microenvironment to enhance bone regeneration. This review aims to clarify the components of the bone regeneration microenvironment, the application of HMS in bone regeneration, and the associated mechanisms. It also discusses various preparation materials and methods of HMS and their applications in bone tissue engineering. Furthermore, it elaborates on the relevant mechanisms by which HMS regulates the physiological, chemical, and physical microenvironment in bone regeneration to achieve bone regeneration. Finally, we discuss the future prospects of the HMS system application for comprehensive regulation of bone regeneration microenvironment, to provide novel perspectives for the research and application of HMS in the bone tissue engineering field.
Bone, cartilage, and soft tissue regeneration is a complex process involving many cellular activities across various cell types. Autografts remain the “gold standard” for the regeneration of these tissues. However, the use of autografts is associated with many disadvantages, including donor scarcity, the requirement of multiple surgeries, and the risk of infection. The development of tissue engineering techniques opens new avenues for enhanced tissue regeneration. Nowadays, the expectations of tissue engineering scaffolds have gone beyond merely providing physical support for cell attachment. Ideal scaffolds should also provide biological cues to actively boost tissue regeneration. As a new type of injectable biomaterial, hydrogel microspheres have been increasingly recognised as promising therapeutic carriers for the local delivery of cells and drugs to enhance tissue regeneration. Compared to traditional tissue engineering scaffolds and bulk hydrogel, hydrogel microspheres possess distinct advantages, including less invasive delivery, larger surface area, higher transparency for visualisation, and greater flexibility for functionalisation. Herein, we review the materials characteristics of hydrogel microspheres and compare their fabrication approaches, including microfluidics, batch emulsion, electrohydrodynamic spraying, lithography, and mechanical fragmentation. Additionally, based on the different requirements for bone, cartilage, nerve, skin, and muscle tissue regeneration, we summarize the applications of hydrogel microspheres as cell and drug delivery carriers for the regeneration of these tissues. Overall, hydrogel microspheres are regarded as effective therapeutic delivery carriers to enhance tissue regeneration in regenerative medicine. However, significant effort is required before hydrogel microspheres become widely accepted as commercial products for clinical use.
The treatment of bone defects remains a great clinical challenge. With the development of science and technology, bone tissue engineering technology has emerged, which can mimic the structure and function of natural bone tissues and create solutions for repairing or replacing human bone tissues based on biocompatible materials, cells and bioactive factors. Hydrogels are favoured by researchers due to their high water content, degradability and good biocompatibility. This paper describes the hydrogel sources, roles and applications. According to the different types of stimuli, hydrogels are classified into three categories: physical, chemical and biochemical responses, and the applications of different stimuli-responsive hydrogels in bone tissue engineering are summarised. Stimuli-responsive hydrogels can form a semi-solid with good adhesion based on different physiological environments, which can carry a variety of bone-enhancing bioactive factors, drugs and cells, and have a long retention time in the local area, which is conducive to a long period of controlled release; they can also form a scaffold for constructing tissue repair, which can jointly promote the repair of bone injury sites. However, it also has many defects, such as poor biocompatibility, immunogenicity and mechanical stability. Further studies are still needed in the future to facilitate its clinical translation.
The treatment and repair of bone tissue damage and loss due to infection, tumours, and trauma are major challenges in clinical practice. Artificial bone scaffolds offer a safer, simpler, and more feasible alternative to bone transplantation, serving to fill bone defects and promote bone tissue regeneration. Ideally, these scaffolds should possess osteoconductive, osteoinductive, and osseointegrative properties. However, the current first-generation implants, represented by titanium alloys, have shown poor bone-implant integration performance and cannot meet the requirements for bone tissue repair. This has led to increased research on second and third generation artificial bone scaffolds, which focus on loading bioactive molecules and cells. Polymer microspheres, known for their high specific surface areas at the micro- and nanoscale, exhibit excellent cell and drug delivery behaviours. Additionally, with their unique rigid structure, microsphere scaffolds can be constructed using methods such as thermal sintering, injection, and microsphere encapsulation. These scaffolds not only ensure the excellent cell drug loading performance of microspheres but also exhibit spatial modulation behaviour, aiding in bone repair within a three-dimensional network structure. This article provides a summary and discussion of the use of polymer microsphere scaffolds for bone repair, focusing on the mechanisms of bone tissue repair and the current status of clinical bone grafts, aimed at advancing research in bone repair.
With the rapid development of population ageing, bone-related diseases seriously affecting the life of the elderly. Over the past few years, organoids, cell clusters with specific functions and structures that are self-induced from stem cells after three-dimensional culture in vitro, have been widely used for bone therapy. Moreover, organoid extracellular vesicles (OEVs) have emerging as promising cell-free nanocarriers due to their vigoroso physiological effects, significant biological functions, stable loading capacity, and great biocompatibility. In this review, we first provide a comprehensive overview of biogenesis, internalisation, isolation, and characterisation of OEVs. We then comprehensively highlight the differences between OEVs and traditional EVs. Subsequently, we present the applications of natural OEVs in disease treatment. We also summarise the engineering modifications of OEVs, including engineering parental cells and engineering OEVs after isolation. Moreover, we provide an outlook on the potential of natural and engineered OEVs in bone-related diseases. Finally, we critically discuss the advantages and challenges of OEVs in the treatment of bone diseases. We believe that a comprehensive discussion of OEVs will provide more innovative and efficient solutions for complex bone diseases.
Recent advances in neuroelectrode interface materials and modification technologies are reviewed. Brain-computer interface is the new method of human-computer interaction, which not only can realise the exchange of information between the human brain and external devices, but also provides a brand-new means for the diagnosis and treatment of brain-related diseases. The neural electrode interface part of brain-computer interface is an important area for electrical, optical and chemical signal transmission between brain tissue system and external electronic devices, which determines the performance of brain-computer interface. In order to solve the problems of insufficient flexibility, insufficient signal recognition ability and insufficient biocompatibility of traditional rigid electrodes, researchers have carried out extensive studies on the neuroelectrode interface in terms of materials and modification techniques. This paper introduces the biological reactions that occur in neuroelectrodes after implantation into brain tissue and the decisive role of the electrode interface for electrode function. Following this, the latest research progress on neuroelectrode materials and interface materials is reviewed from the aspects of neuroelectrode materials and modification technologies, firstly taking materials as a clue, and then focusing on the preparation process of neuroelectrode coatings and the design scheme of functionalised structures.
Infection and rejection in musculoskeletal trauma often pose challenges for natural healing, prompting the exploration of biomimetic organ and tissue transplantation as a common alternative solution. Polyhydroxyalkanoates (PHAs) are a large family of biopolyesters synthesised in microorganism, demonstrating excellent biocompatibility and controllable biodegradability for tissue remodelling and drug delivery. With different monomer-combination and polymer-types, multi-mechanical properties of PHAs making them have great application prospects in medical devices with stretching, compression, twist in long time, especially in musculoskeletal tissue engineering. This review systematically summarises the applications of PHAs in multiple tissues repair and drug release, encompassing areas such as bone, cartilage, joint, skin, tendons, ligament, cardiovascular tissue, and nervous tissue. It also discusses challenges encountered in their application, including high production costs, potential cytotoxicity, and uncontrollable particle size distribution. In conclusion, PHAs offer a compelling avenue for musculoskeletal system applications, striking a balance between biocompatibility and mechanical performance. However, addressing challenges in their production and application requires further research to unleash their full potential in tackling the complexities of musculoskeletal regeneration.
While bone tissue is known for its inherent regenerative abilities, various pathological conditions and trauma can disrupt its meticulously regulated processes of bone formation and resorption. Bone tissue engineering aims to replicate the extracellular matrix of bone tissue as well as the sophisticated biochemical mechanisms crucial for effective regeneration. Traditionally, the field has relied on external agents like growth factors and pharmaceuticals to modulate these processes. Although efficacious in certain scenarios, this strategy is compromised by limitations such as safety issues and the transient nature of the compound release and half-life. Conversely, bioactive elements such as zinc (Zn), magnesium (Mg) and silicon (Si), have garnered increasing interest for their therapeutic benefits, superior stability, and reduced biotic risks. Moreover, these elements are often incorporated into biomaterials that function as multifaceted bioactive components, facilitating bone regeneration via release on-demand. By elucidating the mechanistic roles and therapeutic efficacy of the bioactive elements, this review aims to establish bioactive elements as a robust and clinically viable strategy for advanced bone regeneration.
Periodontitis is a prevalent oral disease. It can cause tooth loss and has a significant impact on patients’ quality of life. While existing treatments can only slow the progression of periodontitis, they are unable to achieve complete regeneration and functional reconstruction of periodontal tissues. As a result, regenerative therapies based on biomaterials have become a focal point of research in the field of periodontology. Despite numerous studies reporting the superiority of new materials in periodontal regeneration, limited progress has been made in translating these findings into clinical practice. This may be due to the lack of appropriate animal models to simulate the tissue defects caused by human periodontitis. This review aims to provide an overview of established animal models for periodontal regeneration, examine their advantages and limitations, and outline the steps for model construction. The objective is to determine the most relevant animal models for periodontal regeneration based on the hypothesis and expected outcomes.
The growing field of dental implant research and development has emerged to rectify the problems associated with human dental health issues. Bio–ceramics are widely used in the medical field, particularly in dental implants, ortho implants, and medical and surgical tools. Various materials have been used in those applications to overcome the limitations and problems associated with their performance and its impact on dental implants. In this article we review and describe the fabrication methods employed for ceramic composites, the microstructure analyses used to identify significant effects on fracture behaviour, and various methods of enhancing mechanical properties. Further, the collective data show that the sintering technique improves the density, hardness, fracture toughness, and flexural strength of alumina– and zirconia–based composites compared with other methods. Future research aspects and suggestions are discussed systematically.
With continuous developments in additive manufacturing technology, tantalum (Ta) metal has been manufactured into orthopaedic implants with a variety of forms, properties and uses by three–dimensional printing. Based on extensive research in recent years, the design, processing and performance aspects of this new orthopaedic implant material have been greatly improved. Besides the bionic porous structure and mechanical characteristics that are similar to human bone tissue, porous tantalum is considered to be a viable bone repair material due to its outstanding corrosion resistance, biocompatibility, bone integration and bone conductivity. Numerous in vitro, in vivo, and clinical studies have been carried out in order to analyse the safety and efficacy of these implants in orthopaedic applications. This study reviews the most recent advances in manufacturing, characteristics and clinical application of porous tantalum materials.
Oncolytic virus (OV) therapy has been shown to be an effective targeted cancer therapy treatment in recent years, providing an avenue of treatment that poses no damage to surrounding healthy tissues. Not only do OVs cause direct oncolysis, but they also amplify both innate and adaptive immune responses generating long-term anti-tumour immunity. Genetically engineered OVs have become the common promising strategy to enhance anti-tumour immunity, safety, and efficacy as well as targeted delivery. The studies of various OVs have been accomplished through phase I-III clinical trial studies. In addition, the uses of carrier platforms of organic materials such as polymer chains, liposomes, hydrogels, and cell carriers have played a vital role in the potentially targeted delivery of OVs. The mechanism, rational design, recent clinical trials, applications, and the development of targeted delivery platforms of OVs will be discussed in this review.
Entheses are highly specialised organs connecting ligaments and tendons to bones, facilitating force transmission, and providing mechanical strengths to absorb forces encountered. Two types of entheses, fibrocartilaginous and fibrous, exist in interfaces. The gradual fibrocartilaginous type is in rotator cuff tendons and is more frequently injured due to the poor healing capacity that leads to loss of the original structural and biomechanical properties and is attributed to the high prevalence of retears. Fluctuating methodologies and outcomes of biological approaches are challenges to overcome for them to be routinely used in clinics. Therefore, stratifying the existing literature according to different categories (chronicity, extent of tear, and studied population) would effectively guide repair approaches. This literature review supports tissue engineering approaches to promote rotator cuff enthesis healing employing cells, growth factors, and scaffolds period. Outcomes suggest its promising role in animal studies as well as some clinical trials and that combination therapies are more beneficial than individualized ones. It then highlights the importance of tailoring interventions according to the tear extent, chronicity, and the population being treated. Contributing factors such as loading, deficiencies, and lifestyle habits should also be taken into consideration. Optimum results can be achieved if biological, mechanical, and environmental factors are approached. It is challenging to determine whether variations are due to the interventions themselves, the animal models, loading regimen, materials, or tear mechanisms. Future research should focus on tailoring interventions for different categories to formulate protocols, which would best guide regenerative medicine decision making.
Cancer is a serious concern in public health worldwide. Numerous modalities including surgery, radiotherapy, and chemotherapy, have been used for cancer therapies in clinic. Despite progress in anticancer therapies, the usage of these methods for cancer treatment is often related to deleterious side effects and multidrug resistance of conventional anticancer drugs, which have prompted the development of novel therapeutic methods. Anticancer peptides (ACPs), derived from naturally occurring and modified peptides, have received great attention in these years and emerge as novel therapeutic and diagnostic candidates for cancer therapies, because of several advantages over the current treatment modalities. In this review, the classification and properties of ACPs, the mode of action and mechanism of membrane disruption, as well as the natural sources of bioactive peptides with anticancer activities were summarised. Because of their high efficacy for inducing cancer cell death, certain ACPs have been developed to work as drugs and vaccines, evaluated in varied phases of clinical trials. We expect that this summary could facilitate the understanding and design of ACPs with increased specificity and toxicity towards malignant cells and with reduced side effects to normal cells.
Mechanobiological study of chondrogenic cells and multipotent stem cells for articular cartilage tissue engineering (CTE) has been widely explored. The mechanical stimulation in terms of wall shear stress, hydrostatic pressure and mechanical strain has been applied in CTE in vitro. It has been found that the mechanical stimulation at a certain range can accelerate the chondrogenesis and articular cartilage tissue regeneration. This review explicitly focuses on the study of the influence of the mechanical environment on proliferation and extracellular matrix production of chondrocytes in vitro for CTE. The multidisciplinary approaches used in previous studies and the need for in silico methods to be used in parallel with in vitro methods are also discussed. The information from this review is expected to direct facial CTE research, in which mechanobiology has not been widely explored yet.
Hydrogen sulfide (H2S) has been reported as an endogenous gasotransmitter that contributes to the modulation of a myriad of biological signalling pathways, which includes maintaining homeostasis in living organisms at physiological concentrations, controlling protein sulfhydration and persulfidation for signalling processes, mediating neurodegeneration, and regulating inflammation and innate immunity, etc. As a result, researchers are actively exploring effective approaches to evaluate the properties and the distribution of H2S in vivo. Furthermore, the regulation of the physiological conditions of H2S in vivo introduces the opportunity to further study the molecular mechanisms by which H2S regulates cellular functions. In recent years, many H2S–releasing compounds and biomaterials that can deliver H2S to various body systems have been developed to provide sustained and stable H2S delivery. Additionally, various designs of these H2S–releasing biomaterials have been proposed to aid in the normal conduction of physiological processes, such as cardioprotection and wound healing, by modulating different signalling pathways and cell functionalities. Using biomaterials as a platform to control the delivery of H2S introduces the opportunity to fine tune the physiological concentration of H2S in vivo, a key to many therapeutic applications. In this review, we highlight recent research works concerning the development and application of H2S–releasing biomaterials with a special emphasis to different release triggering conditions in in vivo studies. We believe that the further exploration of the molecular mechanisms underlying H2S donors and their function when incorporated with various biomaterials will potentially help us understand the pathophysiological mechanisms of different diseases and assist the development of H2S–based therapies.
Clinical therapeutics for the regeneration of osteochondral defects (OCD) in the early stages of osteoarthritis remain an enormous challenge in orthopaedics. For in-depth studies of tissue engineering and regenerative medicine in terms of OCD treatment, the utility of an optimal OCD animal model is crucial for assessing the effects of implanted biomaterials on the repair of damaged osteochondral tissues. Currently, the most frequently used in vivo animal models for OCD regeneration include mice, rats, rabbits, dogs, pigs, goats, sheep, horses and nonhuman primates. However, there is no single “gold standard” animal model to accurately recapitulate human disease in all aspects, thus understanding the benefits and limitations of each animal model is critical for selecting the most suitable one. In this review, we aim to elaborate the complex pathological changes in osteoarthritic joints and to summarise the advantages and limitations of OCD animal models utilised for biomaterial testing along with the methodology of outcome assessment. Furthermore, we review the surgical procedures of OCD creation in different species, and the novel biomaterials that promote OCD regeneration. Above all, it provides a significant reference for selection of an appropriate animal model for use in preclinical in vivo studies of biomaterial-assisted osteochondral regeneration in osteoarthritic joints.
Tissue–resident stem cells are a group of stem cells distinguished by their capacity for self–renewal and multilineage differentiation capability with tissue specificity. Among these tissue–resident stem cells, skeletal stem cells (SSCs) were discovered in the growth plate region through a combination of cell surface markers and lineage tracing series. With the process of unravelling the anatomical variation of SSCs, researchers were also keen to investigate the developmental diversity outside the long bones, including in the sutures, craniofacial sites, and spinal regions. Recently, fluorescence–activated cell sorting, lineage tracing, and single–cell sequencing have been used to map lineage trajectories by studying SSCs with different spatiotemporal distributions. The SSC niche also plays a pivotal role in regulating SSC fate, such as cell–cell interactions mediated by multiple signalling pathways. This review focuses on discussing the spatial and temporal distribution of SSCs, and broadening our understanding of the diversity and plasticity of SSCs by summarizing the progress of research into SSCs in recent years.
Accumulating evidence suggests that the therapeutic role of mesenchymal stem cells (MSCs) in bone diseases is closely related to paracrine–generated extracellular vesicles (EVs). MSC–derived EVs (MSC–EVs) carry proteins, nucleic acids, and lipids to the extracellular space and affect the bone microenvironment. They have similar biological functions to MSCs, such as the ability to repair organ and tissue damage. In addition, MSC–EVs also have the advantages of long half–life, low immunogenicity, attractive stability, ability to pass through the blood–brain barrier, and demonstrate excellent performance with potential practical applications in bone diseases. In this review, we summarise the current applications and mechanisms of MSC–EVs in osteoporosis, osteoarthritis, bone tumours, osteonecrosis of the femoral head, and fractures, as well as the development of MSC–EVs combined with materials science in the field of orthopaedics. Additionally, we explore the critical challenges involved in the clinical application of MSC–EVs in orthopaedic diseases.
Diabetic wounds are a common complication in diabetes patients. Due to peripheral nerve damage and vascular dysfunction, diabetic wounds are prone to progress to local ulcers, wound gangrene and even to require amputation, bringing huge psychological and economic burdens to patients. However, the current treatment methods for diabetic wounds mainly include wound accessories, negative pressure drainage, skin grafting and surgery; there is still no ideal treatment to promote diabetic wound healing at present. Appropriate animal models can simulate the physiological mechanism of diabetic wounds, providing a basis for translational research in treating diabetic wound healing. Although there are no animal models that can fully mimic the pathophysiological mechanisms of diabetic wounds in humans, it is vital to explore animal simulation models used in basic research and preclinical studies of diabetic wounds. In addition, hydrogel materials are regarded as a promising treatment for diabetic wounds because of their good antimicrobial activity, biocompatibility, biodegradation and appropriate mechanical properties. Herein, we review and discuss the different animal models used to investigate the pathological mechanisms of diabetic wounds. We further discuss the promising future application of hydrogel biomaterials in diabetic wound healing.
Microorganisms with innate and artificial advantages have been regarded as intelligent drug delivery systems for cancer therapy with the help of engineering technology. Although numerous studies have confirmed the promising prospects of microorganisms in cancer, several problems such as immunogenicity and toxicity should be addressed before further clinical applications. This review aims to investigate the development of engineered microorganism–based delivery systems for targeted cancer therapy. The main types of microorganisms such as bacteria, viruses, fungi, microalgae, and their components and characteristics are introduced in detail. Moreover, the engineering strategies and biomaterials design of microorganisms are further discussed. Most importantly, we discuss the innovative attempts and therapeutic effects of engineered microorganisms in cancer. Taken together, engineered microorganism–based delivery systems hold tremendous promise for biomedical applications in targeted cancer therapy.
Cartilage injuries are common problems that increase with the population aging. Cartilage is an avascular tissue with a relatively low level of cellular mitotic activity, which makes it impossible to heal spontaneously. To compensate for this problem, three-dimensional bio-printing has attracted a great deal of attention in cartilage tissue engineering. This emerging technology aims to create three-dimensional functional scaffolds by accurately depositing layer-by-layer bio-inks composed of biomaterial and cells. As a novel bio-ink, a decellularized extracellular matrix can serve as an appropriate substrate that contains all the necessary biological cues for cellular interactions. Here, this review is intended to provide an overview of decellularized extracellular matrix-based bio-inks and their properties, sources, and preparation process. Following this, decellularized extracellular matrix-based bio-inks for cartilage tissue engineering are discussed, emphasizing cell behavior and in-vivo applications. Afterward, the current challenges and future outlook will be discussed to determine the conclusing remarks.
Polyether-ether-ketone (PEEK) is believed to be the next-generation biomedical material for orthopaedic implants that may replace metal materials because of its good biocompatibility, appropriate mechanical properties and radiolucency. Currently, some PEEK implants have been used successfully for many years. However, there is no customised PEEK orthopaedic implant made by additive manufacturing licensed for the market, although clinical trials have been increasingly reported. In this review article, design criteria, including geometric matching, functional restoration, strength safety, early fixation, long-term stability and manufacturing capability, are summarised, focusing on the clinical requirements. An integrated framework of design and manufacturing processes to create customised PEEK implants is presented, and several typical clinical applications such as cranioplasty patches, rib prostheses, mandibular prostheses, scapula prostheses and femoral prostheses are described. The main technical challenge faced by PEEK orthopaedic implants lies in the poor bonding with bone and soft tissue due to its biological inertness, which may be solved by adding bioactive fillers and manufacturing porous architecture. The lack of technical standards is also one of the major factors preventing additive-manufactured customised PEEK orthopaedic implants from clinical translation, and it is good to see that the abundance of standards in the field of additive-manufactured medical devices is helping them enter the clinical market.
Based on studies over the last several decades, the self-renewing skeletal lineages derived from bone marrow stroma could be an ideal source for skeletal tissue engineering. However, the markers for osteogenic precursors; i.e., bone marrow-derived skeletal stem cells (SSCs), in association with other cells of the marrow stroma (bone marrow stromal cells, BMSCs) and their heterogeneous nature both in vivo and in vitro remain to be clarified. This review aims to highlight: i) the importance of distinguishing BMSCs/SSCs from other “mesenchymal stem/stromal cells”, and ii) factors that are responsible for their heterogeneity, and how these factors impact on the differentiation potential of SSCs towards bone. The prospective role of SSC enrichment, their expansion and its impact on SSC phenotype is explored. Emphasis has also been given to emerging single cell RNA sequencing approaches in scrutinizing the unique population of SSCs within the BMSC population, along with their committed progeny. Understanding the factors involved in heterogeneity may help researchers to improvise their strategies to isolate, characterize and adopt best culture practices and source identification to develop standard operating protocols for developing reproducible stem cells grafts. However, more scientific understanding of the molecular basis of heterogeneity is warranted that may be obtained from the robust high-throughput functional transcriptomics of single cells or clonal populations.
Recent advances in the field of stem cell research now enable their utilisation for biotechnology applications in regenerative medicine and food tech. The first use of stem cells as biomedical devices employed a combination of cells and scaffold to restore, improve, or replace damaged tissues and to grow new viable tissue for replacement organs. This approach has also been adopted to replace meat production in the food industry. Mesenchymal stem cells are the source material used to induce cells to differentiate into the desired lineage. These technologies require mass propagation and rely on supplying the regulatory factors that direct differentiation. Mesenchymal stem cells can differentiate into fibroblastic and skeletal cells; fibroblastic/chondrogenic/osteogenic/myogenic and adipogenic lineages. Each differentiation fate requires specific key molecular regulators and appropriate activation conditions. Stem cell commitment determination involves a concerted effort of coordinated activation and silencing of lineage-specific genes. Transcription factors which bind gene promoters and chromatin-remodelling proteins are key players in the control process of lineage commitment and differentiation from embryogenesis through adulthood. Consequently, a major research challenge is to characterise such molecular pathways that coordinate lineage-specific differentiation and function. Revealing the mechanisms of action and the main factors will provide the knowledge necessary to control activation and regulation to achieve a specific lineage. Growing cells on a scaffold is a support system that mimics natural tissue and transduces the appropriate signals of the tissue niche for appropriate cellular function. The outcome of such research will deepen the understanding of cell differentiation to promote and advance the biotech, allowing the cell expansion required for their usage in therapy or the development of food tech.
The teeth and their supporting tissues provide an easily accessible source of oral stem cells. These different stem cell populations have been extensively studied for their properties, such as high plasticity and clonogenicity, expressing stem cell markers and potency for multilineage differentiation in vitro. Such cells with stem cell properties have been derived and characterised from the dental pulp tissue, the apical papilla region of roots in development, as well as the supporting tissue of periodontal ligament that anchors the tooth within the alveolar socket and the soft gingival tissue. Studying the dental pulp stem cell populations in a continuously growing mouse incisor model, as a traceable in vivo model, enables the researchers to study the properties, origin and behaviour of mesenchymal stem cells. On the other side, the oral mucosa with its remarkable scarless wound healing phenotype, offers a model to study a well-coordinated system of healing because of coordinated actions between epithelial, mesenchymal and immune cells populations. Although described as homogeneous cell populations following their in vitro expansion, the increasing application of approaches that allow tracing of individual cells over time, along with single-cell RNA-sequencing, reveal that different oral stem cells are indeed diverse populations and there is a highly organised map of cell populations according to their location in resident tissues, elucidating diverse stem cell niches within the oral tissues. This review covers the current knowledge of diverse oral stem cells, focusing on the new approaches in studying these cells. These approaches “decode” and “map” the resident cells populations of diverse oral tissues and contribute to a better understanding of the “stem cells niche architecture and interactions. Considering the high accessibility and simplicity in obtaining these diverse stem cells, the new findings offer potential in development of translational tissue engineering approaches and innovative therapeutic solutions.
Haematopoietic microenvironmental niches have been described as the ‘gatekeepers’ for the blood and immune systems. These niches change during ontogeny, with the bone marrow becoming the predominant site of haematopoiesis in post-natal life under steady state conditions. To determine the structure and function of different haematopoietic microenvironmental niches, it is essential to clearly define specific haematopoietic stem and progenitor cell subsets during ontogeny and to understand their temporal appearance and anatomical positioning. A variety of haematopoietic and non-haematopoietic cells contribute to haematopoietic stem and progenitor cell niches. The latter is reported to include endothelial cells and mesenchymal stromal cells (MSCs), skeletal stem cells and/or C-X-C motif chemokine ligand 12-abundant-reticular cell populations, which form crucial components of these microenvironments under homeostatic conditions. Dysregulation or deterioration of such cells contributes to significant clinical disorders and diseases worldwide and is associated with the ageing process. A critical appraisal of these issues and of the roles of MSC/C-X-C motif chemokine ligand 12-abundant-reticular cells and the more recently identified skeletal stem cell subsets in bone marrow haematopoietic niche function under homeostatic conditions and during ageing will form the basis of this research review. In the context of haematopoiesis, clinical translation will deal with lessons learned from the vast experience garnered from the development and use of MSC therapies to treat graft versus host disease in the context of allogeneic haematopoietic transplants, the recent application of these MSC therapies to treating emerging and severe coronavirus disease 2019 (COVID-19) infections, and, given that skeletal stem cell ageing is one proposed driver for haematopoietic ageing, the potential contributions of these stem cells to haematopoiesis in healthy bone marrow and the benefits and challenges of using this knowledge for rejuvenating the age-compromised bone marrow haematopoietic niches and restoring haematopoiesis.
Stem cells have been one of the ideal sources for tissue regeneration owing to their capability of self-renewal and differentiation. In vivo, the extracellular microenvironment plays a vital role in modulating stem cell fate. When developing biomaterials for regenerative medicine, incorporating biochemical and biophysical cues to mimic extracellular matrix can enhance stem cell lineage differentiation. More specifically, modulating the stem cell fate can be achieved by controlling the nanotopographic features on synthetic surfaces. Optimization of nanotopographical features leads to desirable stem cell functions, which can maximize the effectiveness of regenerative treatment. In this review, nanotopographical surfaces, including static patterned surface, dynamic patterned surface, and roughness are summarized, and their fabrication, as well as the impact on stem cell behaviour, are discussed. Later, the recent progress of applying nanotopographical featured biomaterials for altering different types of stem cells is presented, which directs the design and fabrication of functional biomaterial. Last, the perspective in fundamental research and for clinical application in this field is discussed.
Bone grafts have traditionally come from four sources: the patients’ own tissue (autograft), tissue from a living or cadaveric human donor (allograft), animal donors (xenograft) and synthetic artificial biomaterials (ceramics, cement, polymers, and metal). However, all of these have advantages and drawbacks. The most commercially successful bone grafts so far are allografts, which hold 57% of the current bone graft market; however, disease transmission and scarcity are still significant drawbacks limiting their use. Tissue-engineered grafts have great potential, in which human stem cells and synthetical biomaterials are combined to produce bone-like tissue in vitro, but this is yet to be approved for widespread clinical practice. It is hypothesised that artificial bone allografts can be mass-manufactured to replace conventional bone allografts through refined bone tissue engineering prior to decellularisation. This review article aims to review current literature on (1) conventional bone allograft preparation; (2) bone tissue engineering including the use of synthetic biomaterials as bone graft substitute scaffolds, combined with osteogenic stem cells in vitro; (3) potential artificial allograft manufacturing processes, including mass production of engineered bone tissue, osteogenic enhancement, decellularisation, sterilisation and safety assurance for regulatory approval. From these assessments, a practical route map for mass production of artificial allografts for clinical use is proposed.
Cardiovascular disease serves as the leading cause of death worldwide, with stenosis, occlusion, or severe dysfunction of blood vessels being its pathophysiological mechanism. Vascular replacement is the preferred surgical option for treating obstructed vascular structures. Due to the limited availability of healthy autologous vessels as well as the incidence of postoperative complications, there is an increasing demand for artificial blood vessels. From synthetic to natural, or a mixture of these components, numerous materials have been used to prepare artificial vascular grafts. Although synthetic grafts are more appropriate for use in medium to large-diameter vessels, they fail when replacing small-diameter vessels. Tissue-engineered vascular grafts are very likely to be an ideal alternative to autologous grafts in small-diameter vessels and are worthy of further investigation. However, a multitude of problems remain that must be resolved before they can be used in biomedical applications. Accordingly, this review attempts to describe these problems and provide a discussion of the generation of artificial blood vessels. In addition, we deliberate on current state-of-the-art technologies for creating artificial blood vessels, including advances in materials, fabrication techniques, various methods of surface modification, as well as preclinical and clinical applications. Furthermore, the evaluation of grafts both in vivo and in vitro, mechanical properties, challenges, and directions for further research are also discussed.
Human embryonic stem cells and induced pluripotent stem cells, together denoted as pluripotent stem cells have opened up unprecedented opportunities for developments in human healthcare over the past 20 years. Although much about the properties and behaviour of these cells required to underpin their applications has been discovered over this time, a number of issues remain. This brief review considers the history of these developments and some of the underlying biology, pointing out some of the problems still to be resolved, particularly in relation to their genetic stability and possible malignancy.
Microphysiological systems (MPS) created with human-derived cells and biomaterial scaffolds offer a potential in vitro alternative to in vivo animal models. The adoption of three-dimensional MPS models has economic, ethical, regulatory, and scientific implications for the fields of regenerative medicine, metabolism/obesity, oncology, and pharmaceutical drug discovery. Key opinion leaders acknowledge that MPS tools are uniquely positioned to aid in the objective to reduce, refine, and eventually replace animal experimentation while improving the accuracy of the finding’s clinical translation. Adipose tissue has proven to be an accessible and available source of human-derived stromal vascular fraction (SVF) cells, a heterogeneous population available at point of care, and adipose-derived stromal/stem cells, a relatively homogeneous population requiring plastic adherence and culture expansion of the SVF cells. The adipose-derived stromal/stem cells or SVF cells, in combination with human tissue or synthetic biomaterial scaffolds, can be maintained for extended culture periods as three-dimensional MPS models under angiogenic, stromal, adipogenic, or osteogenic conditions. This review highlights recent literature relating to the versatile use of adipose-derived cells as fundamental components of three-dimensional MPS models for discovery research and development. In this context, it compares the merits and limitations of the adipose-derived stromal/stem cells relative to SVF cell models and considers the likely directions that this emerging field of scientific discovery will take in the near future.
