| Musculoskeletal injury is a very common disease.There are about 30 million tendon/ligament-related clinical operations each year worldwide,which brings huge medical burden and economic cost to society.The interface tissues(enthesis)in the musculoskeletal system,such as bone-ligament,bone-tendon,and bone-cartilage interface tissues,have a specific structure and function and play a key role in absorbing impact and reducing stress concentration during exercise.Currently,ACL reconstruction is the main treatment for knee ligament injury.However,due to the special biomolecular composition,microstructure,and micromechanics of the interface tissue,surgical reconstruction of ruptured ligament/tendon often creates new bone-graft interfaces with mismatched properties,leading to poor osseointegration and an overall increase in the rate of graft failure.Therefore,the current problems make it more urgent and necessary to develop a new strategy for interface tissue repair and regeneration.Biomaterials is an attractive approach to improve the healing and regeneration of tissue.On the one hand,the morphological structure of biomaterials can be designed similar to that of natural extracellular matrix(ECM),providing adhesion sites and matrix platform for cell adhesion,growth,differentiation,and tissue formation.On the other hand,the physicochemical properties and biological activities of biomaterials could improve the microenvironment of injured tissues with no toxicity or side effects.At the same time,biomaterials can also regulate the tissue healing process,promoting tissue regeneration and functional recovery.In particular,nanofiber biomaterials have attracted extensive attention due to their advantages,such as high specific surface area,large porosity,adjustability of fiber diameter,simplicity of surface functional modification,and ECM-like morphology and structure.However,nanofiber materials still have some shortcomings for application in interface tissue engineering:(1)How to design the biomaterials with good biocompatibility matching the natural interface tissues.So that they not only have the components and structural characteristics of natural tissues but also have the biological functions of guiding interface tissue regeneration.(2)How to design the biomaterials that can respond to the tissue repair process.So that in the early repair stage,the biomaterials can effectively inhibit inflammation and accelerate the transition from the inflammatory phase to the subsequent processes.And in the middle and late stages,they could support cell proliferation and differentiation,promote the regeneration and restore of the fibrocartilage,achieving effective integration of tendon-bone and functional recovery of interface tissue.On consideration of the above background,the purpose of this article is to promote regeneration of interface tissue,achieve the effective integration of tendon-bone and the recovery of biological functions.In this article,a theory of construction for biomimetic-functional nanofiber scaffolds was proposed: according to the structure characteristics and repair process of interface tissue,selective functionalization on the nanofiber surface can regulate the interface microenvironment,guide tissue regeneration and functional recovery.Based on this,three kinds of functional nanofiber scaffolds are designed and fabricated by using natural silk fibroin(SF).Their physicochemical properties and biological functions are evaluated with a series of in vitro and in vivo experiments in order to provide scientific reference and guidance for the research and development of interface tissue engineering biomaterials and clinical application transformation.The main contents and conclusions of this article are as follows:1)Fabrication of reductive nanofibers with anti-inflammatory properties for tendon-bone integration.To reduce the oxidative stress and inflammatory response caused by excessive reactive oxygen species(ROS)after injuries in the interface tissue and accelerate the transition from the inflammatory stage to the middle and late stages of the tissue healing process,a ROS scavenging nanofiber with inflammatory regulation was constructed based on SF nanofiber in this chapter.Then the physicochemical properties of the scaffolds were characterized and the ROS scavenging ability of the nanofibers was verified by detecting intracellular ROS levels.Finally,in vivo experiments were conducted to investigate the inflammatory regulation of the nanofibers.The results showed that the mechanical properties,hydrophilicity,and cell adhesion of the nanofiber scaffold were significantly enhanced with polydopamine(PD)surface modification.At the same time,the reductive nanofiber scaffold can effectively reduce the intracellular ROS level,improve the cellular activity in the oxidative stress environment,and significantly reduce the inflammatory response at the early stage of interface tissue repair stage in vivo.2)Fabrication of multi-functionalized nanofibers with fibrocartilage inductivity for tendon-bone integration.To further improve the regeneration microenvironment of the interface tissue in the middle and late stages,a multifunctional nanofiber scaffold with a drug sustained-release function was constructed in this chapter,where the reductive nanofiber scaffolds were used as drug carriers and the amino groups of PD were used as the binding sites.The fabricated nanofibers could not only effectively reduce inflammation in the early stage of the enthesis healing process but also enhance fibrocartilage formation in the later stages.These functions are ascribed to the excellent antioxidant activity of PD and the fibrochondrogenic inductivity of kartogenin(KGN)at the interface.The multifunctional nanofibers show good biocompatibility,excellent anti-inflammatory effects and can accelerate the regeneration of interface tissue and improve the integration of tendon-bone as demonstrated with both in vitro and in vivo results.Combining antioxidant activity with inductive stimulus on extracellular matrix-like biomaterials will provide valuable insight into an efficient strategy of tissue regeneration and functional recovery for clinical applications in interface tissue engineering.3)Fabrication of gradient biomineralized nanofibers with osteochondral inductivity for tendon-bone integration.Enthesis injury repair remains a huge challenge because of the unique biomolecular composition,microstructure,and mechanics in the interfacial region.Surgical reconstruction often creates new bone-scaffold interfaces with mismatched properties,resulting in poor osseointegration.To mimic the natural interface tissue structures and properties,we fabricated a nanofibrous scaffold with gradient mineral coating based on 10× simulated body fluid(SBF)and SF.We then characterized the physicochemical properties of the scaffolds and identified the effects of different levels of mineralization on bone marrow mesenchymal stem cell attachment,growth,and differentiation.The results show that a high level of mineralization can upregulate the osteoblast-specific gene expression significantly,whereas a low level of mineralization can upregulate COL2A1 and Sox9 gene expression.Furthermore,we established an in vivo model in rats,and the results show that the gradient scaffolds exhibited an enhancement of integration in the tendon-to-bone interface with a higher ultimate load and more fibrocartilage-like tissue formation.These findings demonstrate that the silk-based nanofibrous scaffold with gradient mineral coating can regulate the formation of interface tissue and has the potential to be applied in interface tissue engineering.In this article,a theory of construction for biomimetic-functional nanofibers was proposed,and three kinds of nanofiber scaffolds with different functions were designed and fabricated based on the process of interface tissue repair and regeneration,which is an important research focus in interface tissue engineering.These multi-functionalized nanofibers had good biocompatibility and excellent biological activities,could regulate the repair process with their physicochemical properties and biological activities,promote the integration of tendon-bone,and recover the biological functions of interface tissue.These findings could provide research ideas and references for the design and development of clinical biomaterials and have great potential applications in interface tissue engineering. |
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