Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages,ultimately impairing its normal physiological function.A...Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages,ultimately impairing its normal physiological function.Accumulating evidence underscores the potential of targeted modulation of mechanical cues to enhance skin regeneration,promoting scarless repair by influencing the extracellular microenvironment and driving the phenotypic transitions.The field of skin repair and skin appendage regeneration has witnessed remarkable advancements in the utilization of biomaterials with distinct physical properties.However,a comprehensive understanding of the underlying mechanisms remains somewhat elusive,limiting the broader application of these innovations.In this review,we present two promising biomaterial-based mechanical approaches aimed at bolstering the regenerative capacity of compromised skin.The first approach involves leveraging biomaterials with specific biophysical properties to create an optimal scarless environment that supports cellular activities essential for regeneration.The second approach centers on harnessing mechanical forces exerted by biomaterials to enhance cellular plasticity,facilitating efficient cellular reprogramming and,consequently,promoting the regeneration of skin appendages.In summary,the manipulation of mechanical cues using biomaterial-based strategies holds significant promise as a supplementary approach for achieving scarless wound healing,coupled with the restoration of multiple skin appendage functions.展开更多
As the global population ages,osteoporotic bone fractures leading to bone defects are increasingly becoming a significant challenge in the field of public health.Treating this disease faces many challenges,especially ...As the global population ages,osteoporotic bone fractures leading to bone defects are increasingly becoming a significant challenge in the field of public health.Treating this disease faces many challenges,especially in the context of an imbalance between osteoblast and osteoclast activities.Therefore,the development of new biomaterials has become the key.This article reviews various design strategies and their advantages and disadvantages for biomaterials aimed at osteoporotic bone defects.Overall,current research progress indicates that innovative design,functionalization,and targeting of materials can significantly enhance bone regeneration under osteoporotic conditions.By comprehensively considering biocompatibility,mechanical properties,and bioactivity,these biomaterials can be further optimized,offering a range of choices and strategies for the repair of osteoporotic bone defects.展开更多
Following the discovery of bone as an endocrine organ with systemic influence,bone-brain interaction has emerged as a research hotspot,unveiling complex bidirectional communication between bone and brain.Studies indic...Following the discovery of bone as an endocrine organ with systemic influence,bone-brain interaction has emerged as a research hotspot,unveiling complex bidirectional communication between bone and brain.Studies indicate that bone and brain can influence each other’s homeostasis via multiple pathways,yet there is a dearth of systematic reviews in this area.This review comprehensively examines interactions across three key areas:the influence of bone-derived factors on brain function,the effects of brain-related diseases or injuries(BRDI)on bone health,and the concept of skeletal interoception.Additionally,the review discusses innovative approaches in biomaterial design inspired by bone-brain interaction mechanisms,aiming to facilitate bonebrain interactions through materiobiological effects to aid in the treatment of neurodegenerative and bone-related diseases.Notably,the integration of artificial intelligence(AI)in biomaterial design is highlighted,showcasing AI’s role in expediting the formulation of effective and targeted treatment strategies.In conclusion,this review offers vital insights into the mechanisms of bone-brain interaction and suggests advanced approaches to harness these interactions in clinical practice.These insights offer promising avenues for preventing and treating complex diseases impacting the skeleton and brain,underscoring the potential of interdisciplinary approaches in enhancing human health.展开更多
Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to p...Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks. In neural tissue engineering, manipulation of biomaterial stiffness is a promising strategy to provide a permissive environment for the repair and regeneration of injured nervous tissue. Recent research has fine-tuned synthetic biomaterials to fabricate scaffolds that closely replicate the stiffness profiles observed in the nervous system. In this review, we highlight the molecular mechanisms by which extracellular matrix stiffness regulates axonal growth and regeneration. We highlight the progress made in the development of stiffness-tunable biomaterials to emulate in vivo extracellular matrix environments, with an emphasis on their application in neural repair and regeneration, along with a discussion of the current limitations and future prospects. The exploration and optimization of the stiffness-tunable biomaterials has the potential to markedly advance the development of neural tissue engineering.展开更多
The incidence of large bone defects caused by traumatic injury is increasing worldwide,and the tissue regeneration process requires a long recovery time due to limited self-healing capability.Endogenous bioelectrical ...The incidence of large bone defects caused by traumatic injury is increasing worldwide,and the tissue regeneration process requires a long recovery time due to limited self-healing capability.Endogenous bioelectrical phenomena have been well recognized as critical biophysical factors in bone remodeling and regeneration.Inspired by bioelectricity,electrical stimulation has been widely considered an external intervention to induce the osteogenic lineage of cells and enhance the synthesis of the extracellular matrix,thereby accelerating bone regeneration.With ongoing advances in biomaterials and energy-harvesting techniques,electroactive biomaterials and self-powered systems have been considered biomimetic approaches to ensure functional recovery by recapitulating the natural electrophysiological microenvironment of healthy bone tissue.In this review,we first introduce the role of bioelectricity and the endogenous electric field in bone tissue and summarize different techniques to electrically stimulate cells and tissue.Next,we highlight the latest progress in exploring electroactive hybrid biomaterials as well as self-powered systems such as triboelectric and piezoelectric-based nanogenerators and photovoltaic cell-based devices and their implementation in bone tissue engineering.Finally,we emphasize the significance of simulating the target tissue’s electrophysiological microenvironment and propose the opportunities and challenges faced by electroactive hybrid biomaterials and self-powered bioelectronics for bone repair strategies.展开更多
Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied fo...Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.展开更多
Neural injuries can be induced by various neurological disorders and traumas,such as brain and spinal cord injuries,cerebrovascular diseases,and neurodegeneration.Due to the designable physicochemical properties,bioma...Neural injuries can be induced by various neurological disorders and traumas,such as brain and spinal cord injuries,cerebrovascular diseases,and neurodegeneration.Due to the designable physicochemical properties,biomaterials are applied for various purposes in neural repair,including promoting axonal regeneration,reducing glial scar formation,delivering drugs,and providing temporary mechanical support to the injured tissue.They need to match the extracellular matrix(ECM)environment,support threedimensional(3D)cell growth,repair the cellular microenvironment,mimic the tissue's biomechanical forces,and possess biodegradability and plasticity suitable for local intracavity applications.Meanwhile,functionalized biomaterials have been conducted to mimic the structural components of cellular ecological niches and the specific functions of the ECM.They can be engineered to carry a variety of bioactive components,such as stem cells and extracellular vesicles,which are used in neuroscience-related tissue engineering.Researchers also have developed biomaterial-based brain-like organs for high-throughput drug screening and pathological mechanistic studies.This review will discuss the interactions between biomaterials and cells,as well as the advances in neural injuries and engineered microtissues.展开更多
Endometrial injury caused by repeated uterine procedures,infections,inflammation,or uterine artery dysfunction can deplete endometrial stem/progenitor cells and impair regeneration,thereby diminishing endometrial rece...Endometrial injury caused by repeated uterine procedures,infections,inflammation,or uterine artery dysfunction can deplete endometrial stem/progenitor cells and impair regeneration,thereby diminishing endometrial receptivity and evidently lowering the live birth,clinical pregnancy,and embryo implantation rates.Currently,safe and effective clinical treatment methods or gene-targeted therapies are unavailable,especially for severe endometrial injury.Umbilical cord mesenchymal stem cells and their extracellular vesicles are characterized by their simple collection,rapid proliferation,low immunogenicity,and tumorigenicity,along with their involvement in regulating angiogenesis,immune response,cell apoptosis and proliferation,inflammatory response,and fibrosis,Therefore,these cells and vesicles hold broad potential for application in endometrial repair.This article reviewed recent research on human umbilical cord mesenchymal stem cells as well as their extracellular vesicles in repairing endometrial injury.展开更多
The treatment of skin wounds,especially chronic wounds,remains a critical clinical challenge and places a heavy burden on patients and healthcare systems.In recent years,the engineering strategy of using biomaterial-a...The treatment of skin wounds,especially chronic wounds,remains a critical clinical challenge and places a heavy burden on patients and healthcare systems.In recent years,the engineering strategy of using biomaterial-assisted exosomes has emerged as a powerful tool for skin repair.Compared to treatments such as debridement and regular dressing changes,the design of biomaterial-assisted exosomes not only maintains the bioactivity of exosomes at the wound site but also provides an appropriate microenvironment for the repair of complex tissues,thereby accelerating wound healing.This review systematically introduces the general characteristics of exosomes and their functions in skin wound healing,highlights recent advances in classification of natural exosomes and engineering methods which enriching their functions in intercellular communication.Then,various emerging and innovative approaches based on biomaterials delivery of exosomes are comprehensively discussed.The review seeks to bring an in-depth understanding of bioactive dressings based on exosomes therapeutic strategies,aiming to facilitate new clinical application value.展开更多
Bone injuries induced by accidents or bone-related disease have dramatically increased in the past decades.The application of biomaterials has become an inextricable part of treatment for new bone formation and regene...Bone injuries induced by accidents or bone-related disease have dramatically increased in the past decades.The application of biomaterials has become an inextricable part of treatment for new bone formation and regeneration.Different from traditional bone-regeneration materials,injectable biomaterials—ranging from bioceramics to polymers—have been applied as a means of promoting surgery with a minimal intervention approach.In this review,we summarize the most recent developments in minimally invasive implantable biomaterials for bone reconstruction and different ways to achieve osteogenesis,with a focus on injectable biomaterials for various applications in the orthopedic field.More specifically,bioceramics and polymeric materials,together with their applications in bone fracture healing,vertebral body augmentation,bone implant fixation,bone tumor therapy,and bone-defect-related infection treatment are reviewed in detail.Recent progress in injectable biomaterials with multiple functionalities and bioresponsive properties is also reviewed.Finally,we summarize the challenges in this field and future directions for clinical treatment.展开更多
BACKGROUND Bone regeneration is a central focus of regenerative medicine,with applications in orthopedics and dentistry,particularly for treating bone defects caused by trauma,infection,or congenital anomalies.Synthet...BACKGROUND Bone regeneration is a central focus of regenerative medicine,with applications in orthopedics and dentistry,particularly for treating bone defects caused by trauma,infection,or congenital anomalies.Synthetic biomaterials,often combined with fibrin derivatives,offer promising solutions for bone healing and restoration.AIM To Explore the increasingly important role of the association of synthetic biomaterials with fibrin in bone regeneration.METHODS Search terms included:“synthetic biomaterials AND fibrin sealant”,“hydroxyapatite AND fibrin sealant”,“tricalcium phosphate AND fibrin sealant”,and“synthetic biomaterials AND platelet-rich fibrin(PRF)”,resulting in 67 articles.After rigorous screening,21 articles met the inclusion criteria.RESULTS The reviewed studies assessed biomaterials like hydroxyapatite(HA),β-tricalcium phosphate(β-TCP),and fibrin-based products.Key findings highlighted the enhanced osteoconductivity and biocompatibility of HA andβ-TCP,especially when combined with fibrin sealants.These composites show significant potential for improving cellular adhesion,promoting osteogenic differentiation,and accelerating bone regeneration.The antimicrobial properties and structural support for cell growth of certain biomaterials indicate a promising potential for clinical applic-ations.CONCLUSION This systematic review emphasizes the growing role of fibrin-based biomaterials in bone regeneration and urges continued research to improve their clinical use for complex bone defects.展开更多
Bone defects caused by trauma,infection,or congenital anomalies remain a significant challenge in orthopedic and dental practice,necessitating innovative strategies to enhance healing and functional restoration.This s...Bone defects caused by trauma,infection,or congenital anomalies remain a significant challenge in orthopedic and dental practice,necessitating innovative strategies to enhance healing and functional restoration.This systematic review by Pagani et al synthesizes evidence on the synergistic role of synthetic biomaterials,such as hydroxyapatite(HA)andβ-tricalcium phosphate(β-TCP),combined with fibrin derivatives in bone regeneration.Analyzing 21 studies,the authors demonstrate that HA andβ-TCP composites exhibit superior osteoconductivity and biocompatibility when integrated with fibrin sealants or plateletrich fibrin,promoting cellular adhesion,osteogenic differentiation,and accelerated healing.While these studies underscore the potential of these biomaterialfibrin hybrids,limitations such as variability in fibrin preparation,lack of longterm data,and insufficient standardization hinder clinical translation.This editorial contextualizes these findings within the evolving landscape of regenerative medicine,emphasizing the need for optimized formulations,interdisciplinary collaboration,and robust clinical trials to bridge laboratory innovation to bedside application.展开更多
Accumulating research has shed light on the significance of skeletal interoception,in maintaining physiological and metabolic homeostasis related to bone health.This review provides a comprehensive analysis of how ske...Accumulating research has shed light on the significance of skeletal interoception,in maintaining physiological and metabolic homeostasis related to bone health.This review provides a comprehensive analysis of how skeletal interoception influences bone homeostasis,delving into the complex interplay between the nervous system and skeletal system.One key focus of the review is the role of various factors such as prostaglandin E2(PGE2)in skeletal health via skeletal interoception.It explores how nerves innervating the bone tissue communicate with the central nervous system to regulate bone remodeling,a process critical for maintaining bone strength and integrity.Additionally,the review highlights the advancements in biomaterials designed to utilize skeletal interoception for enhancing bone regeneration and treatment of bone disorders.These biomaterials,tailored to interact with the body’s interoceptive pathways,are positioned at the forefront of innovative treatments for conditions like osteoporosis and fractures.They represent a convergence of bioengineering,neuroscience,and orthopedics,aiming to create more efficient and targeted therapies for bone-related disorders.In conclusion,the review underscores the importance of skeletal interoception in physiological regulation and its potential in developing more effective therapies for bone regeneration.It emphasizes the need for further research to fully understand the mechanisms of skeletal interoception and to harness its therapeutic potential fully.展开更多
Flexible sensors,a class of devices that can convert external mechanical or physical signals into changes in resistance,capacitance,or current,have developed rapidly since the concept was first proposed.Due to the spe...Flexible sensors,a class of devices that can convert external mechanical or physical signals into changes in resistance,capacitance,or current,have developed rapidly since the concept was first proposed.Due to the special properties and naturally occurring excellent microstructures of biomaterials,it can provide more desirable properties to flexible devices.This paper systematically discusses the commonly used biomaterials for bio-based flexible devices in current research applications and their deployment in preparing flexible sensors with different mechanisms.According to the characteristics of other properties and application requirements of biomaterials,the mechanisms of their functional group properties,special microstructures,and bonding interactions in the context of various sensing applications are presented in detail.The practical application scenarios of biomaterial-based flexible devices are highlighted,including human-computer interactions,energy harvesting,wound healing,and related biomedical applications.Finally,this paper also reviews in detail the limitations of biobased materials in the construction of flexible devices and presents challenges and trends in the development of biobased flexible sensors,as well as to better explore the properties of biomaterials to ensure functional synergy within the composite materials.展开更多
Introduction When the body is infected,pathogenic microorganisms and their toxins can enter the blood circulation and grow and proliferate in the blood,producing more toxins.These toxins and pathogens activate the bod...Introduction When the body is infected,pathogenic microorganisms and their toxins can enter the blood circulation and grow and proliferate in the blood,producing more toxins.These toxins and pathogens activate the body's immune system,leading to the release of a varieties of cytokines and inflammatory mediators,resulting in systemic inflammatory response syndrome[1].展开更多
Enhancing neurological recovery and improving the prognosis of spinal cord injury have gained research attention recently.Spinal cord injury is associated with a complex molecular and cellular microenvironment.This co...Enhancing neurological recovery and improving the prognosis of spinal cord injury have gained research attention recently.Spinal cord injury is associated with a complex molecular and cellular microenvironment.This complexity has prompted researchers to elucidate the underlying pathophysiological mechanisms and changes and to identify effective treatment strategies.Traditional approaches for spinal cord injury repair include surgery,oral or intravenous medications,and administration of neurotrophic factors;however,the efficacy of these approaches remains inconclusive,and serious adverse reactions continue to be a concern.With advancements in tissue engineering and regenerative medicine,emerging strategies for spinal cord injury repair now involve nanoparticle-based nanodelivery systems,scaffolds,and functional recovery techniques that incorporate biomaterials,bioengineering,stem cell,and growth factors as well as three-dimensional bioprinting.Ideal biomaterial scaffolds should not only provide structural support for neuron migration,adhesion,proliferation,and differentiation but also mimic the mechanical properties of natural spinal cord tissue.Additionally,these scaffolds should facilitate axon growth and neurogenesis by offering adjustable topography and a range of physical and biochemical cues.The three-dimensionally interconnected porous structure and appropriate physicochemical properties enabled by three-dimensional biomimetic printing technology can maximize the potential of biomaterials used for treating spinal cord injury.Therefore,correct selection and application of scaffolds,coupled with successful clinical translation,represent promising clinical objectives to enhance the treatment efficacy for and prognosis of spinal cord injury.This review elucidates the key mechanisms underlying the occurrence of spinal cord injury and regeneration post-injury,including neuroinflammation,oxidative stress,axon regeneration,and angiogenesis.This review also briefly discusses the critical role of nanodelivery systems used for repair and regeneration of injured spinal cord,highlighting the influence of nanoparticles and the factors that affect delivery efficiency.Finally,this review highlights tissue engineering strategies and the application of biomaterial scaffolds for the treatment of spinal cord injury.It discusses various types of scaffolds,their integrations with stem cells or growth factors,and approaches for optimization of scaffold design.展开更多
Magnesium(Mg)alloys are promising candidates for biodegradable implants and medical devices due to their biocompatibility,mechanical properties,and ability to degrade in vivo,thereby eliminating the need for secondary...Magnesium(Mg)alloys are promising candidates for biodegradable implants and medical devices due to their biocompatibility,mechanical properties,and ability to degrade in vivo,thereby eliminating the need for secondary removal surgeries[1,2].However,their clinical adoption is hindered by rapid corrosion in physiological environments[3–5].Due to the high chemical reactivity of magnesium substrates and the inability of primary corrosion degradation products to form ideal protective layers,no effective scientific guidance has yet been identified from fundamental material science to address the rapid degradation of bare Mg[6–8].Surface modification strategies equivalently create new materials wrapped in a matrix,which can thus be extensively explored to enhance the corrosion resistance of Mg alloys while endowing them with tailored biological functionalities[9,10].展开更多
Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people...Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people are diagnosed with SCI annually(Singh et al.,2014),and while this number appears quite low,the effect that an SCI has on the patient’s quality of life is drastic,due to the current difficulties to comprehensively treat this illness.The cost of patient care can also be quite costly,amounting to an estimated$1.69 billion in healthcare costs in the USA alone(Mahabaleshwarkar and Khanna,2014).展开更多
Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering(TE)and regenerative medicine.In contrast to conventional biomaterials or synthetic materials,biomimetic scaffolds bas...Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering(TE)and regenerative medicine.In contrast to conventional biomaterials or synthetic materials,biomimetic scaffolds based on natural biomaterial can offer cells a broad spectrum of biochemical and biophysical cues that mimic the in vivo extracellular matrix(ECM).Additionally,such materials have mechanical adaptability,micro-structure interconnectivity,and inherent bioactivity,making them ideal for the design of living implants for specific applications in TE and regenerative medicine.This paper provides an overview for recent progress of biomimetic natural biomaterials(BNBMs),including advances in their preparation,functionality,potential applications and future challenges.We highlight recent advances in the fabrication of BNBMs and outline general strategies for functionalizing and tailoring the BNBMs with various biological and physicochemical characteristics of native ECM.Moreover,we offer an overview of recent key advances in the functionalization and applications of versatile BNBMs for TE applications.Finally,we conclude by offering our perspective on open challenges and future developments in this rapidly-evolving field.展开更多
Traumatic brain injury is a serious medical condition that can be attributed to falls, motor vehicle accidents, sports injuries and acts of violence, causing a series of neural injuries and neuropsychiatric symptoms. ...Traumatic brain injury is a serious medical condition that can be attributed to falls, motor vehicle accidents, sports injuries and acts of violence, causing a series of neural injuries and neuropsychiatric symptoms. However, limited accessibility to the injury sites, complicated histological and anatomical structure, intricate cellular and extracellular milieu, lack of regenerative capacity in the native cells, vast variety of damage routes, and the insufficient time available for treatment have restricted the widespread application of several therapeutic methods in cases of central nervous system injury. Tissue engineering and regenerative medicine have emerged as innovative approaches in the field of nerve regeneration. By combining biomaterials, stem cells, and growth factors, these approaches have provided a platform for developing effective treatments for neural injuries, which can offer the potential to restore neural function, improve patient outcomes, and reduce the need for drugs and invasive surgical procedures. Biomaterials have shown advantages in promoting neural development, inhibiting glial scar formation, and providing a suitable biomimetic neural microenvironment, which makes their application promising in the field of neural regeneration. For instance, bioactive scaffolds loaded with stem cells can provide a biocompatible and biodegradable milieu. Furthermore, stem cells-derived exosomes combine the advantages of stem cells, avoid the risk of immune rejection, cooperate with biomaterials to enhance their biological functions, and exert stable functions, thereby inducing angiogenesis and neural regeneration in patients with traumatic brain injury and promoting the recovery of brain function. Unfortunately, biomaterials have shown positive effects in the laboratory, but when similar materials are used in clinical studies of human central nervous system regeneration, their efficacy is unsatisfactory. Here, we review the characteristics and properties of various bioactive materials, followed by the introduction of applications based on biochemistry and cell molecules, and discuss the emerging role of biomaterials in promoting neural regeneration. Further, we summarize the adaptive biomaterials infused with exosomes produced from stem cells and stem cells themselves for the treatment of traumatic brain injury. Finally, we present the main limitations of biomaterials for the treatment of traumatic brain injury and offer insights into their future potential.展开更多
基金supported in part by the National Nature Science Foundation of China(92268206,81830064)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)+4 种基金the Military Medical Research Projects(145AKJ260015000X,2022-JCJQ-ZB-09600)the Military Key Basic Research of Foundational Strengthening Program(2020-JCJQ-ZD-256-021)the Science Foundation of National Defense Science and Technology for Excellent Young(2022-JCJQ-ZQ-017)the Military Medical Research and Development Projects(AWS17J005,2019-126)the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province(YSPTZX202317).
文摘Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages,ultimately impairing its normal physiological function.Accumulating evidence underscores the potential of targeted modulation of mechanical cues to enhance skin regeneration,promoting scarless repair by influencing the extracellular microenvironment and driving the phenotypic transitions.The field of skin repair and skin appendage regeneration has witnessed remarkable advancements in the utilization of biomaterials with distinct physical properties.However,a comprehensive understanding of the underlying mechanisms remains somewhat elusive,limiting the broader application of these innovations.In this review,we present two promising biomaterial-based mechanical approaches aimed at bolstering the regenerative capacity of compromised skin.The first approach involves leveraging biomaterials with specific biophysical properties to create an optimal scarless environment that supports cellular activities essential for regeneration.The second approach centers on harnessing mechanical forces exerted by biomaterials to enhance cellular plasticity,facilitating efficient cellular reprogramming and,consequently,promoting the regeneration of skin appendages.In summary,the manipulation of mechanical cues using biomaterial-based strategies holds significant promise as a supplementary approach for achieving scarless wound healing,coupled with the restoration of multiple skin appendage functions.
基金supported by the National Natural Science Foundation of China(Nos.82160419 and 82302772)Guizhou Basic Research Project(No.ZK[2023]General 201)。
文摘As the global population ages,osteoporotic bone fractures leading to bone defects are increasingly becoming a significant challenge in the field of public health.Treating this disease faces many challenges,especially in the context of an imbalance between osteoblast and osteoclast activities.Therefore,the development of new biomaterials has become the key.This article reviews various design strategies and their advantages and disadvantages for biomaterials aimed at osteoporotic bone defects.Overall,current research progress indicates that innovative design,functionalization,and targeting of materials can significantly enhance bone regeneration under osteoporotic conditions.By comprehensively considering biocompatibility,mechanical properties,and bioactivity,these biomaterials can be further optimized,offering a range of choices and strategies for the repair of osteoporotic bone defects.
基金financially supported by the Basic Science Center Program(T2288102)the Key Program of the National Natural Science Foundation of China(32230059)+3 种基金the Foundation of Frontiers Science Center for Materiobiology and Dynamic Chemistry(JKVD1211002)the Project supported by the Young Scientists Fund of the National Natural Science Foundation of China(32401128)Postdoctoral Fellowship Program of CPSF(GZC20230793)Shanghai Post-doctoral Excellence Program(2023251).
文摘Following the discovery of bone as an endocrine organ with systemic influence,bone-brain interaction has emerged as a research hotspot,unveiling complex bidirectional communication between bone and brain.Studies indicate that bone and brain can influence each other’s homeostasis via multiple pathways,yet there is a dearth of systematic reviews in this area.This review comprehensively examines interactions across three key areas:the influence of bone-derived factors on brain function,the effects of brain-related diseases or injuries(BRDI)on bone health,and the concept of skeletal interoception.Additionally,the review discusses innovative approaches in biomaterial design inspired by bone-brain interaction mechanisms,aiming to facilitate bonebrain interactions through materiobiological effects to aid in the treatment of neurodegenerative and bone-related diseases.Notably,the integration of artificial intelligence(AI)in biomaterial design is highlighted,showcasing AI’s role in expediting the formulation of effective and targeted treatment strategies.In conclusion,this review offers vital insights into the mechanisms of bone-brain interaction and suggests advanced approaches to harness these interactions in clinical practice.These insights offer promising avenues for preventing and treating complex diseases impacting the skeleton and brain,underscoring the potential of interdisciplinary approaches in enhancing human health.
基金supported by the Natio`nal Natural Science Foundation of China,No. 81801241a grant from Sichuan Science and Technology Program,No. 2023NSFSC1578Scientific Research Projects of Southwest Medical University,No. 2022ZD002 (all to JX)。
文摘Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks. In neural tissue engineering, manipulation of biomaterial stiffness is a promising strategy to provide a permissive environment for the repair and regeneration of injured nervous tissue. Recent research has fine-tuned synthetic biomaterials to fabricate scaffolds that closely replicate the stiffness profiles observed in the nervous system. In this review, we highlight the molecular mechanisms by which extracellular matrix stiffness regulates axonal growth and regeneration. We highlight the progress made in the development of stiffness-tunable biomaterials to emulate in vivo extracellular matrix environments, with an emphasis on their application in neural repair and regeneration, along with a discussion of the current limitations and future prospects. The exploration and optimization of the stiffness-tunable biomaterials has the potential to markedly advance the development of neural tissue engineering.
基金support of the National Natural Science Foundation of China(Grant No.52205593)Shaanxi Natural Science Foundation Project(2024JC-YBMS-711).
文摘The incidence of large bone defects caused by traumatic injury is increasing worldwide,and the tissue regeneration process requires a long recovery time due to limited self-healing capability.Endogenous bioelectrical phenomena have been well recognized as critical biophysical factors in bone remodeling and regeneration.Inspired by bioelectricity,electrical stimulation has been widely considered an external intervention to induce the osteogenic lineage of cells and enhance the synthesis of the extracellular matrix,thereby accelerating bone regeneration.With ongoing advances in biomaterials and energy-harvesting techniques,electroactive biomaterials and self-powered systems have been considered biomimetic approaches to ensure functional recovery by recapitulating the natural electrophysiological microenvironment of healthy bone tissue.In this review,we first introduce the role of bioelectricity and the endogenous electric field in bone tissue and summarize different techniques to electrically stimulate cells and tissue.Next,we highlight the latest progress in exploring electroactive hybrid biomaterials as well as self-powered systems such as triboelectric and piezoelectric-based nanogenerators and photovoltaic cell-based devices and their implementation in bone tissue engineering.Finally,we emphasize the significance of simulating the target tissue’s electrophysiological microenvironment and propose the opportunities and challenges faced by electroactive hybrid biomaterials and self-powered bioelectronics for bone repair strategies.
文摘Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.
基金supported by the National Natural Science Foundation of China(No.82273487)the Young Medical Scientists Training Program(No.21QNPY051)the Shanghai Integration Achievement Program(No.2022-RH17)。
文摘Neural injuries can be induced by various neurological disorders and traumas,such as brain and spinal cord injuries,cerebrovascular diseases,and neurodegeneration.Due to the designable physicochemical properties,biomaterials are applied for various purposes in neural repair,including promoting axonal regeneration,reducing glial scar formation,delivering drugs,and providing temporary mechanical support to the injured tissue.They need to match the extracellular matrix(ECM)environment,support threedimensional(3D)cell growth,repair the cellular microenvironment,mimic the tissue's biomechanical forces,and possess biodegradability and plasticity suitable for local intracavity applications.Meanwhile,functionalized biomaterials have been conducted to mimic the structural components of cellular ecological niches and the specific functions of the ECM.They can be engineered to carry a variety of bioactive components,such as stem cells and extracellular vesicles,which are used in neuroscience-related tissue engineering.Researchers also have developed biomaterial-based brain-like organs for high-throughput drug screening and pathological mechanistic studies.This review will discuss the interactions between biomaterials and cells,as well as the advances in neural injuries and engineered microtissues.
文摘Endometrial injury caused by repeated uterine procedures,infections,inflammation,or uterine artery dysfunction can deplete endometrial stem/progenitor cells and impair regeneration,thereby diminishing endometrial receptivity and evidently lowering the live birth,clinical pregnancy,and embryo implantation rates.Currently,safe and effective clinical treatment methods or gene-targeted therapies are unavailable,especially for severe endometrial injury.Umbilical cord mesenchymal stem cells and their extracellular vesicles are characterized by their simple collection,rapid proliferation,low immunogenicity,and tumorigenicity,along with their involvement in regulating angiogenesis,immune response,cell apoptosis and proliferation,inflammatory response,and fibrosis,Therefore,these cells and vesicles hold broad potential for application in endometrial repair.This article reviewed recent research on human umbilical cord mesenchymal stem cells as well as their extracellular vesicles in repairing endometrial injury.
基金financially supported by the National Natural Science Foundation of China(No.82030056)Postdoctoral Innovation Talents Support Program of China(No.BX20230489)。
文摘The treatment of skin wounds,especially chronic wounds,remains a critical clinical challenge and places a heavy burden on patients and healthcare systems.In recent years,the engineering strategy of using biomaterial-assisted exosomes has emerged as a powerful tool for skin repair.Compared to treatments such as debridement and regular dressing changes,the design of biomaterial-assisted exosomes not only maintains the bioactivity of exosomes at the wound site but also provides an appropriate microenvironment for the repair of complex tissues,thereby accelerating wound healing.This review systematically introduces the general characteristics of exosomes and their functions in skin wound healing,highlights recent advances in classification of natural exosomes and engineering methods which enriching their functions in intercellular communication.Then,various emerging and innovative approaches based on biomaterials delivery of exosomes are comprehensively discussed.The review seeks to bring an in-depth understanding of bioactive dressings based on exosomes therapeutic strategies,aiming to facilitate new clinical application value.
基金supported by the National Natural Science Foundation of China(81925027,82002275,and 32271421)the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Bone injuries induced by accidents or bone-related disease have dramatically increased in the past decades.The application of biomaterials has become an inextricable part of treatment for new bone formation and regeneration.Different from traditional bone-regeneration materials,injectable biomaterials—ranging from bioceramics to polymers—have been applied as a means of promoting surgery with a minimal intervention approach.In this review,we summarize the most recent developments in minimally invasive implantable biomaterials for bone reconstruction and different ways to achieve osteogenesis,with a focus on injectable biomaterials for various applications in the orthopedic field.More specifically,bioceramics and polymeric materials,together with their applications in bone fracture healing,vertebral body augmentation,bone implant fixation,bone tumor therapy,and bone-defect-related infection treatment are reviewed in detail.Recent progress in injectable biomaterials with multiple functionalities and bioresponsive properties is also reviewed.Finally,we summarize the challenges in this field and future directions for clinical treatment.
文摘BACKGROUND Bone regeneration is a central focus of regenerative medicine,with applications in orthopedics and dentistry,particularly for treating bone defects caused by trauma,infection,or congenital anomalies.Synthetic biomaterials,often combined with fibrin derivatives,offer promising solutions for bone healing and restoration.AIM To Explore the increasingly important role of the association of synthetic biomaterials with fibrin in bone regeneration.METHODS Search terms included:“synthetic biomaterials AND fibrin sealant”,“hydroxyapatite AND fibrin sealant”,“tricalcium phosphate AND fibrin sealant”,and“synthetic biomaterials AND platelet-rich fibrin(PRF)”,resulting in 67 articles.After rigorous screening,21 articles met the inclusion criteria.RESULTS The reviewed studies assessed biomaterials like hydroxyapatite(HA),β-tricalcium phosphate(β-TCP),and fibrin-based products.Key findings highlighted the enhanced osteoconductivity and biocompatibility of HA andβ-TCP,especially when combined with fibrin sealants.These composites show significant potential for improving cellular adhesion,promoting osteogenic differentiation,and accelerating bone regeneration.The antimicrobial properties and structural support for cell growth of certain biomaterials indicate a promising potential for clinical applic-ations.CONCLUSION This systematic review emphasizes the growing role of fibrin-based biomaterials in bone regeneration and urges continued research to improve their clinical use for complex bone defects.
文摘Bone defects caused by trauma,infection,or congenital anomalies remain a significant challenge in orthopedic and dental practice,necessitating innovative strategies to enhance healing and functional restoration.This systematic review by Pagani et al synthesizes evidence on the synergistic role of synthetic biomaterials,such as hydroxyapatite(HA)andβ-tricalcium phosphate(β-TCP),combined with fibrin derivatives in bone regeneration.Analyzing 21 studies,the authors demonstrate that HA andβ-TCP composites exhibit superior osteoconductivity and biocompatibility when integrated with fibrin sealants or plateletrich fibrin,promoting cellular adhesion,osteogenic differentiation,and accelerated healing.While these studies underscore the potential of these biomaterialfibrin hybrids,limitations such as variability in fibrin preparation,lack of longterm data,and insufficient standardization hinder clinical translation.This editorial contextualizes these findings within the evolving landscape of regenerative medicine,emphasizing the need for optimized formulations,interdisciplinary collaboration,and robust clinical trials to bridge laboratory innovation to bedside application.
基金National Natural Science Foundation of China(82230071,82172098)Integrated Project of Major Research Plan of National Natural Science Foundation of China(92249303)+2 种基金Shanghai Committee of Science and Technology(23141900600,Laboratory Animal Research Project)Shanghai Clinical Research Plan of SHDC2023CRT01Young Elite Scientist Sponsorship Program by China Association for Science and Technology(YESS20230049)。
文摘Accumulating research has shed light on the significance of skeletal interoception,in maintaining physiological and metabolic homeostasis related to bone health.This review provides a comprehensive analysis of how skeletal interoception influences bone homeostasis,delving into the complex interplay between the nervous system and skeletal system.One key focus of the review is the role of various factors such as prostaglandin E2(PGE2)in skeletal health via skeletal interoception.It explores how nerves innervating the bone tissue communicate with the central nervous system to regulate bone remodeling,a process critical for maintaining bone strength and integrity.Additionally,the review highlights the advancements in biomaterials designed to utilize skeletal interoception for enhancing bone regeneration and treatment of bone disorders.These biomaterials,tailored to interact with the body’s interoceptive pathways,are positioned at the forefront of innovative treatments for conditions like osteoporosis and fractures.They represent a convergence of bioengineering,neuroscience,and orthopedics,aiming to create more efficient and targeted therapies for bone-related disorders.In conclusion,the review underscores the importance of skeletal interoception in physiological regulation and its potential in developing more effective therapies for bone regeneration.It emphasizes the need for further research to fully understand the mechanisms of skeletal interoception and to harness its therapeutic potential fully.
基金supported financially by the National Natural Science Foundation of China(52205308,22208120)the China Postdoctoral Science Foundation(2022M711300).
文摘Flexible sensors,a class of devices that can convert external mechanical or physical signals into changes in resistance,capacitance,or current,have developed rapidly since the concept was first proposed.Due to the special properties and naturally occurring excellent microstructures of biomaterials,it can provide more desirable properties to flexible devices.This paper systematically discusses the commonly used biomaterials for bio-based flexible devices in current research applications and their deployment in preparing flexible sensors with different mechanisms.According to the characteristics of other properties and application requirements of biomaterials,the mechanisms of their functional group properties,special microstructures,and bonding interactions in the context of various sensing applications are presented in detail.The practical application scenarios of biomaterial-based flexible devices are highlighted,including human-computer interactions,energy harvesting,wound healing,and related biomedical applications.Finally,this paper also reviews in detail the limitations of biobased materials in the construction of flexible devices and presents challenges and trends in the development of biobased flexible sensors,as well as to better explore the properties of biomaterials to ensure functional synergy within the composite materials.
基金supported by the Sichuan Science and Technology Program(2022NSFSC1936)Doctoral Scientific Research Start-up Foundation of China West Normal University(412984).
文摘Introduction When the body is infected,pathogenic microorganisms and their toxins can enter the blood circulation and grow and proliferate in the blood,producing more toxins.These toxins and pathogens activate the body's immune system,leading to the release of a varieties of cytokines and inflammatory mediators,resulting in systemic inflammatory response syndrome[1].
基金supported by the Sichuan Science and Technology Program,No.2023YFS0164(to JC)the National Natural Science Foundation of China,No.82401629(to XL)+1 种基金the Natural Science Foundation of Sichuan Province,No.2024NSFSC1646(to XL)the China Postdoctoral Science Foundation,Nos.GZC20231811(to XL)and 2024T170601(to XL)。
文摘Enhancing neurological recovery and improving the prognosis of spinal cord injury have gained research attention recently.Spinal cord injury is associated with a complex molecular and cellular microenvironment.This complexity has prompted researchers to elucidate the underlying pathophysiological mechanisms and changes and to identify effective treatment strategies.Traditional approaches for spinal cord injury repair include surgery,oral or intravenous medications,and administration of neurotrophic factors;however,the efficacy of these approaches remains inconclusive,and serious adverse reactions continue to be a concern.With advancements in tissue engineering and regenerative medicine,emerging strategies for spinal cord injury repair now involve nanoparticle-based nanodelivery systems,scaffolds,and functional recovery techniques that incorporate biomaterials,bioengineering,stem cell,and growth factors as well as three-dimensional bioprinting.Ideal biomaterial scaffolds should not only provide structural support for neuron migration,adhesion,proliferation,and differentiation but also mimic the mechanical properties of natural spinal cord tissue.Additionally,these scaffolds should facilitate axon growth and neurogenesis by offering adjustable topography and a range of physical and biochemical cues.The three-dimensionally interconnected porous structure and appropriate physicochemical properties enabled by three-dimensional biomimetic printing technology can maximize the potential of biomaterials used for treating spinal cord injury.Therefore,correct selection and application of scaffolds,coupled with successful clinical translation,represent promising clinical objectives to enhance the treatment efficacy for and prognosis of spinal cord injury.This review elucidates the key mechanisms underlying the occurrence of spinal cord injury and regeneration post-injury,including neuroinflammation,oxidative stress,axon regeneration,and angiogenesis.This review also briefly discusses the critical role of nanodelivery systems used for repair and regeneration of injured spinal cord,highlighting the influence of nanoparticles and the factors that affect delivery efficiency.Finally,this review highlights tissue engineering strategies and the application of biomaterial scaffolds for the treatment of spinal cord injury.It discusses various types of scaffolds,their integrations with stem cells or growth factors,and approaches for optimization of scaffold design.
基金supported by grants from the State Key Laboratory for Modification of Chemical Fibers and Polymer Materials,Major/key program(No.23M1060280)the Fundamental Research Funds for the Central Universities(No.2232024D-34 and No 2232023A-10).
文摘Magnesium(Mg)alloys are promising candidates for biodegradable implants and medical devices due to their biocompatibility,mechanical properties,and ability to degrade in vivo,thereby eliminating the need for secondary removal surgeries[1,2].However,their clinical adoption is hindered by rapid corrosion in physiological environments[3–5].Due to the high chemical reactivity of magnesium substrates and the inability of primary corrosion degradation products to form ideal protective layers,no effective scientific guidance has yet been identified from fundamental material science to address the rapid degradation of bare Mg[6–8].Surface modification strategies equivalently create new materials wrapped in a matrix,which can thus be extensively explored to enhance the corrosion resistance of Mg alloys while endowing them with tailored biological functionalities[9,10].
基金supported by the Irish Research Council under the Government of Ireland Postdoctoral Fellowship Project ID-GOIPD/2023/1431(to AS).
文摘Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people are diagnosed with SCI annually(Singh et al.,2014),and while this number appears quite low,the effect that an SCI has on the patient’s quality of life is drastic,due to the current difficulties to comprehensively treat this illness.The cost of patient care can also be quite costly,amounting to an estimated$1.69 billion in healthcare costs in the USA alone(Mahabaleshwarkar and Khanna,2014).
基金supported by the National Natural Science Foundation of China(52003113,31900950,82102334,82002313,82072444)the National Key Research&Development Program of China(2018YFC2001502,2018YFB1105705)+6 种基金the Guangdong Basic and Applied Basic Research Foundation(2021A1515010745,2020A1515110356,2023A1515011986)the Shenzhen Fundamental Research Program(JCYJ20190808120405672)the Key Program of the National Natural Science Foundation of Zhejiang Province(LZ22C100001)the Natural Science Foundation of Shanghai(20ZR1469800)the Integration Innovation Fund of Shanghai Jiao Tong University(2021JCPT03),the Science and Technology Projects of Guangzhou City(202102020359)the Zigong Key Science and Technology Plan(2022ZCNKY07).SXC thanks the financial support under the Startup Grant of the University of Chinese Academy of Sciences(WIUCASQD2021026).HW thanks the Futian Healthcare Research Project(FTWS2022013)the financial support of China Postdoctoral Science Foundation(2021TQ0118).SL thanks the financial support of China Postdoctoral Science Foundation(2022M721490).
文摘Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering(TE)and regenerative medicine.In contrast to conventional biomaterials or synthetic materials,biomimetic scaffolds based on natural biomaterial can offer cells a broad spectrum of biochemical and biophysical cues that mimic the in vivo extracellular matrix(ECM).Additionally,such materials have mechanical adaptability,micro-structure interconnectivity,and inherent bioactivity,making them ideal for the design of living implants for specific applications in TE and regenerative medicine.This paper provides an overview for recent progress of biomimetic natural biomaterials(BNBMs),including advances in their preparation,functionality,potential applications and future challenges.We highlight recent advances in the fabrication of BNBMs and outline general strategies for functionalizing and tailoring the BNBMs with various biological and physicochemical characteristics of native ECM.Moreover,we offer an overview of recent key advances in the functionalization and applications of versatile BNBMs for TE applications.Finally,we conclude by offering our perspective on open challenges and future developments in this rapidly-evolving field.
基金supported by the Sichuan Science and Technology Program,No.2023YFS0164 (to JC)。
文摘Traumatic brain injury is a serious medical condition that can be attributed to falls, motor vehicle accidents, sports injuries and acts of violence, causing a series of neural injuries and neuropsychiatric symptoms. However, limited accessibility to the injury sites, complicated histological and anatomical structure, intricate cellular and extracellular milieu, lack of regenerative capacity in the native cells, vast variety of damage routes, and the insufficient time available for treatment have restricted the widespread application of several therapeutic methods in cases of central nervous system injury. Tissue engineering and regenerative medicine have emerged as innovative approaches in the field of nerve regeneration. By combining biomaterials, stem cells, and growth factors, these approaches have provided a platform for developing effective treatments for neural injuries, which can offer the potential to restore neural function, improve patient outcomes, and reduce the need for drugs and invasive surgical procedures. Biomaterials have shown advantages in promoting neural development, inhibiting glial scar formation, and providing a suitable biomimetic neural microenvironment, which makes their application promising in the field of neural regeneration. For instance, bioactive scaffolds loaded with stem cells can provide a biocompatible and biodegradable milieu. Furthermore, stem cells-derived exosomes combine the advantages of stem cells, avoid the risk of immune rejection, cooperate with biomaterials to enhance their biological functions, and exert stable functions, thereby inducing angiogenesis and neural regeneration in patients with traumatic brain injury and promoting the recovery of brain function. Unfortunately, biomaterials have shown positive effects in the laboratory, but when similar materials are used in clinical studies of human central nervous system regeneration, their efficacy is unsatisfactory. Here, we review the characteristics and properties of various bioactive materials, followed by the introduction of applications based on biochemistry and cell molecules, and discuss the emerging role of biomaterials in promoting neural regeneration. Further, we summarize the adaptive biomaterials infused with exosomes produced from stem cells and stem cells themselves for the treatment of traumatic brain injury. Finally, we present the main limitations of biomaterials for the treatment of traumatic brain injury and offer insights into their future potential.
