Preparation and Properties of Guiqi Polysaccharides/Chitosan/Alginate Composite Hydrogel Microspheres

A series of the Guiqi polysaccharides/chitosan/alginate composite hydrogel microspheres(GPcM)with different particle sizes were prepared with Guiqi polysaccharides(GP),chitosan(CS)and sodium alginate(Alg).The optimum preparation process was also determined by single factor and orthogonal experiment analysis.The GPcM were characterized by fourier transform infrared spectroscopy(FT-IR),scanning electron microscope(SEM),drug loading efficiency test(LE),encapsulation efficiency test(EE)and in vitro release study.The results showed that the Guiqi polysaccharides chitosan hydrogel(GPCH)and sodium alginate hydrogel(SAH)formed a crossover system in GPcM.The GPcM have a uniform particle size ranging from 395.1μm to 841.5μm.The drug loading efficiency and encapsulation efficiency of the GPcM were 56.3%and 72.6%,respectively.The bovine serum albumin(BSA)loaded in the GPcM released slowly within 180 h.The results suggested that the GPcM may have potential application value in drug sustained and controlled release system.

Reprogramming macrophages via immune cell mobilized hydrogel microspheres for osteoarthritis treatments

Regulating macrophage activation precisely is crucial in treating chronic inflammation in osteoarthritis(OA).However,the stable pro-inflammatory state and deep distribution of macrophages in vivo pose a great challenge to treatment.In this study,inspired by the innate immune,immune cell mobilized hydrogel microspheres were constructed by microfluidic methods and load chemokines,macrophage antibodies and engineered cell membrane vesicles(sEVs)via covalent and non-covalent junctions.The immune cell mobilized hydrogel microspheres,based on a mixture of streptavidin grafted hyaluronic acid methacrylate(HAMA-SA)and Chondroitin sulfate methacrylate(ChSMA)microspheres(HCM),can recruit,capture and reprogram proinflammatory macrophages in the joint cavity to improve the joint inflammatory microenvironment.In vitro experiments demonstrated that immune cell mobilized hydrogel microspheres had excellent macrophage recruitment,capture,and reprogramming abilities.Pro-inflammatory macrophages can be transformed into anti-inflammatory macrophages with an efficiency of 88.5%.Animal experiments also revealed significant reduction in synovial inflammation and cartilage matrix degradation of OA.Therefore,the immune cell mobilized hydrogel microspheres may be an effective treatment of OA inflammation for the future.

Cartilage lacuna-biomimetic hydrogel microspheres endowed with integrated biological signal boost endogenous articular cartilage regeneration

Despite numerous studies on chondrogenesis,the repair of cartilage—particularly the reconstruction of cartilage lacunae through an all-in-one advanced drug delivery system remains limited.In this study,we developed a cartilage lacuna-like hydrogel microsphere system endowed with integrated biological signals,enabling sequential immunomodulation and endogenous articular cartilage regeneration.We first integrated the chondrogenic growth factor transforming growth factor-β3(TGF-β3)into mesoporous silica nanoparticles(MSNs).Then,TGF-β3@MSNs and insulin-like growth factor 1(IGF-1)were encapsulated within microspheres made of polydopamine(pDA).In the final step,growth factor-loaded MSN@pDA and a chitosan(CS)hydrogel containing platelet-derived growth factor-BB(PDGF-BB)were blended to produce growth factors loaded composite microspheres(GFs@μS)using microfluidic technology.The presence of pDA reduced the initial acute inflammatory response,and the early,robust release of PDGF-BB aided in attracting endogenous stem cells.Over the subsequent weeks,the continuous release of IGF-1 and TGF-β3 amplified chondrogenesis and matrix formation.μS were incorporated into an acellular cartilage extracellular matrix(ACECM)and combined with a polydopamine-modified polycaprolactone(PCL)structure to produce a tissue-engineered scaffold that mimicked the structure of the cartilage lacunae evenly distributed in the cartilage matrix,resulting in enhanced cartilage repair and patellar cartilage protection.This research provides a strategic pathway for optimizing growth factor delivery and ensuring prolonged microenvironmental remodeling,leading to efficient articular cartilage regeneration.

The use of hydrogel microspheres as cell and drug delivery carriers for bone,cartilage,and soft tissue regeneration

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.

Hydrogel microspheres for bone regeneration through regulation of the regenerative microenvironment

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.

Biomimetic injectable hydrogel microspheres with enhanced lubrication and controllable drug release for the treatment of osteoarthritis

The occurrence of osteoarthritis(OA)is highly associated with the reduced lubrication property of the joint,where a progressive and irreversible damage of the articular cartilage and consecutive inflammatory response dominate the mechanism.In this study,bioinspired by the super-lubrication property of cartilage and catecholamine chemistry of mussel,we successfully developed injectable hydrogel microspheres with enhanced lubrication and controllable drug release for OA treatment.Particularly,the lubricating microspheres(GelMA@DMA-MPC)were fabricated by dip coating a self-adhesive polymer(DMA-MPC,synthesized by free radical copolymerization)on superficial surface of photo-crosslinked methacrylate gelatin hydrogel microspheres(GelMA,prepared via microfluidic technology),and encapsulated with an anti-inflammatory drug of diclofenac sodium(DS)to achieve the dual-functional performance.The tribological test and drug release test showed the enhanced lubrication and sustained drug release of the GelMA@DMA-MPC microspheres.In addition,the functionalized microspheres were intra-articularly injected into the rat knee joint with an OA model,and the biological tests including qRT-PCR,immunofluorescence staining assay,X-ray radiography and histological staining assay all revealed that the biocompatible microspheres provided significant therapeutic effect against the development of OA.In summary,the injectable hydrogel microspheres developed herein greatly improved lubrication and achieved sustained local drug release,therefore representing a facile and promising technique for the treatment of OA.

Exhausted local lactate accumulation via injectable nanozyme-functionalized hydrogel microsphere for inflammation relief and tissue regeneration

Local lactate accumulation greatly hinders tissue repair and regeneration under ischemic condition.Herein,an injectable microsphere(MS@MCL)for local lactate exhaustion was constructed by grafting manganese dioxide(MnO_(2))-lactate oxidase(LOX)composite nanozyme on microfluidic hyaluronic acid methacrylate(HAMA)microspheres via chemical bonds,achieving a long-term oxygen-promoted lactate exhaustion effect and a long half-life in vivo.The uniform and porous microspheres synthesized by microfluidic technology is beneficial to in situ injection therapy and improving encapsulation efficiency.Furthermore,chemical grafting into HAMA microspheres through amide reactions promoted local enzymatic concentration and activity enhancement.It was showed that the MS@MCL eliminated oxidative and inflammatory stress and promoted extracellular matrix metabolism and cell survival when co-cultured with nucleus pulposus cells(NPCs)in vitro.In the rat degenerative intervertebral disc model caused by lactate injection,MS@MCL showed a long-term therapeutic effect in reducing intervertebral height narrowing and preventing extracellular matrix(ECM)degradation as well as inflammatory damage in vivo.Altogether,this study confirms that this nanozyme-functionalized injectable MS@MCL effectively improves the regenerative and reparative effect in ischemic tissues by disposing of enriched lactate in local microenvironment.

Immune-defensive microspheres promote regeneration of the nucleus pulposus by targeted entrapment of the inflammatory cascade during intervertebral disc degeneration

Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration(IVDD).Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the disc.This study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1(TGF-β1)(T-NNPs)onto the surface of methacrylic acid gelatin anhydride microspheres(GM)via amide bonds.The nanoparticle-microsphere complex(GM@T-NNPs)sustained the long-term release of T-NNPs with excellent cell-like functions,effectively bound to pro-inflammatory cytokines,and improved the release kinetics of TGF-β1,maintaining a 36 day-acting release.GM@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro,downregulated the expression of inflammatory factors and matrix metalloproteinase,and upregulated the expression of collagen-II and aggrecan.GM@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD model.The integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.

Fabrication of hollow porous PLGA microspheres for controlled protein release and promotion of cell compatibility

This letter reports on the fabrication of hollow,porous and non-porous poly（D,L-lactide-co-glycolide） （PLGA） microspheres（MSs） for the controlled release of protein and promotion of cell compatibility of tough hydrogels.PLGA MSs with different structures were prepared with modified double emulsion methods,using bovine serum albumin（BSA） as a porogen during emulsification.The release of the residual BSA from PLGA MSs was investigated as a function of the MS structure.The hollow PLGA MSs show a faster protein release than the porous MSs,while the non-porous MSs have the slowest protein release.Compositing the PLGA MSs with poly（vinyl alcohol）（PVA） hydrogels promoted chondrocyte adhesion and proliferation on the hydrogels.

Exosome-loaded biomaterials for tendon/ligament repair

Exosomes,a specialised type of extracellular vesicle,have attracted significant attention in the realm of tendon/ligament repair as a potential biologic therapeutic tool.While the competence of key substances responsible for the delivery function was gradually elucidated,series of shortcomings exemplified by the limited stability still need to be improved.Therefore,how to take maximum advantage of the biological characteristics of exosomes is of great importance.Recently,the comprehensive exploration and application of biomedical engineering has improved the availability of exosomes and revealed the future direction of exosomes combined with biomaterials.This review delves into the present application of biomaterials such as nanomaterials,hydrogels,and electrospun scaffolds,serving as the carriers of exosomes in tendon/ligament repair.By pinpointing and exploring their strengths and limitations,it offers valuable insights,paving the way the future direction of biomaterials in the application of exosomes in tendon/ligament repair in this field.

Biomaterials for microfluidic technology

Micro/nanomaterial-based drug and cell delivery systems play an important role in biomedical fields for their injectability and targeting.Microfluidics is a rapidly developing technology and has become a robust tool for preparing biomaterial micro/nanocarriers with precise structural control and high reproducibility.By flexibly designing microfluidic channels and manipulating fluid behavior,various forms of biomaterial carriers can be fabricated using microfluidics,including microspheres,nanoparticles and microfibers.In this review,recent advances in biomaterials for designing functional microfluidic vehicles are summarized.We introduce the application of natural materials such as polysaccharides and proteins as well as synthetic polymers in the production of microfluidic carriers.How the material properties determine the manufacture of carriers and the type of cargoes to be encapsulated is highlighted.Furthermore,the current limitations of microfluidic biomaterial carriers and perspectives on its future developments are presented.