Dual-crosslinked regenerative hydrogel for sutureless long-term repair of corneal defect

Corneal transplantation is the most effective clinical treatment for corneal defects,but it requires precise size of donor corneas,surgical sutures,and overcoming other technical challenges.Postoperative patients may suffer graft rejection and complications caused by sutures.Ophthalmic glues that can long-term integrate with the corneal tissue and effectively repair the focal corneal damage are highly desirable.Herein,a hybrid hydrogel consisting of porcine decellularized corneal stroma matrix(pDCSM)and methacrylated hyaluronic acid(HAMA)was developed through a non-competitive dual-crosslinking process.It can be directly filled into corneal defects with various shapes.More importantly,through formation of interpenetrating network and stable amide bonds between the hydrogel and adjacent tissue,the hydrogel manifested excellent adhesion properties to achieve suture-free repair.Meanwhile,the hybrid hydrogel not only preserved bioactive components from pDCSM,but also exhibited cornea-matching transparency,low swelling ratio,slow degradation,and enhanced mechanical properties,which was capable of withstanding superhigh intraocular pressure.The combinatorial hydrogel greatly improved the poor cell adhesion performance of HAMA,supported the viability,proliferation of corneal cells,and preservation of keratocyte phenotype.In a rabbit corneal stromal defect model,the experimental eyes treated with the hybrid hydrogel remained transparent and adhered intimately to the stroma bed with long-term retention,accelerated corneal re-epithelialization and wound healing.Giving the advantages of high bioactivity,low-cost,and good practicality,the dual-crosslinked hybrid hydrogel served effectively for long-term suture-free treatment and tissue regeneration after corneal defect.

A comparative study of human and porcine-derived decellularised nerve matrices

Decellularised extracellular matrix(dECM)biomaterials originating from allogeneic and xenogeneic tissues have been broadly studied in the field of regenerative medicine and have already been used in clinical treatments.Allogeneic dECMs are considered more compatible,but they have the drawback of extremely limited human tissue sources.Their availability is also restricted by the health and age of the donors.To investigate the viability of xenogeneic tissues as a substitute for human tissues,we fabricated both porcine decellularised nerve matrix(pDNM)and human decellularised nerve matrix for a comprehensive comparison.Photomicrographs showed that both dECM scaffolds retained the ECM microstructures of native human nerve tissues.Proteomic analysis demonstrated that the protein compositions of both dECMs were also very similar to each other.Their functional ECM contents effectively promoted the proliferation,migration,and maturation of primary human Schwann cells in vitro.However,pDNM contained a few antigens that induced severe host immune responses in humanised mice.Interestingly,after removing theα-galactosidase antigen,the immune responses were highly alleviated and the pre-treated pDNM maintained a human decellularised nerve matrix-like pro-regenerative phenotype.Therefore,we believe that anα-galactosidase-free pDNM may serve as a viable substitute for human decellularised nerve matrix in future clinical applications.

Harnessing decellularised extracellular matrix microgels into modular bioinks for extrusion-based bioprinting with good printability and high post-printing cell viability

The printability of bioink and post-printing cell viability is crucial for extrusion-based bioprinting.A proper bioink not only provides mechanical support for structural fidelity,but also serves as suitable three-dimensional(3D)microenvironment for cell encapsulation and protection.In this study,a hydrogel-based composite bioink was developed consisting of gelatin methacryloyl(GelMA)as the continuous phase and decellularised extracellular matrix microgels(DMs)as the discrete phase.A flow-focusing microfluidic system was employed for the fabrication of cell-laden DMs in a high-throughput manner.After gentle mixing of the DMs and GelMA,both rheological characterisations and 3D printing tests showed that the resulting DM-GelMA hydrogel preserved the shear-thinning nature,mechanical properties,and good printability from GelMA.The integration of DMs not only provided an extracellular matrix-like microenvironment for cell encapsulation,but also considerable shear-resistance for high post-printing cell viability.The DM sizes and inner diameters of the 3D printer needles were correlated and optimised for nozzle-based extrusion.Furthermore,a proof-of-concept bioink composedg of RSC96 Schwann cells encapsulated DMs and human umbilical vein endothelial cell-laden GelMA was successfully bioprinted into 3D constructs,resulting in a modular co-culture system with distinct cells/materials distribution.Overall,the modular DM-GelMA bioink provides a springboard for future precision biofabrication and will serve in numerous biomedical applications such as tissue engineering and drug screening.

Decellularized Disc Hydrogels for hBMSCs tissue-specific differentiation and tissue regeneration

Tissue specificity,a key factor in the decellularized tissue matrix(DTM),has shown bioactive functionalities in tuning cell fate-e.g.,the differentiation of mesenchymal stem cells.Notably,cell fate is also determined by the living microenvironment,including material composition and spatial characteristics.Herein,two neighboring tissues within intervertebral discs,the nucleus pulposus(NP)and annulus fibrosus(AF),were carefully processed into DTM hydrogels(abbreviated DNP-G and DAF-G,respectively)to determine the tissue-specific effects on stem cell fate,such as specific components and different culturing methods,as well as in vivo regeneration.Distinct differences in their protein compositions were identified by proteomic analysis.Interestingly,the fate of human bone marrow mesenchymal stem cells(hBMSCs)also responds to both culturing methods and composition.Generally,hBMSCs cultured with DNP-G(3D)differentiated into NP-like cells,while hBMSCs cultured with DAF-G(2D)underwent AF-like differentiation,indicating a close correlation with the native microenvironments of NP and AF cells,respectively.Furthermore,we found that the integrin-mediated RhoA/LATS/YAP1 signaling pathway was activated in DAF-G(2D)-induced AF-specific differentiation.Additionally,the activation of YAP1 determined the tendency of NP-or AF-specific differentiation and played opposite regulatory effects.Finally,DNP-G and DAF-G specifically promoted tissue regeneration in NP degeneration and AF defect rat models,respectively.In conclusion,DNP-G and DAF-G can specifically determine the fate of stem cells through the integrin-mediated RhoA/LATS/YAP1 signaling pathway,and this tissue specificity is both compositional and spatial,supporting the utilization of tissue-specific DTM in advanced treatments of intervertebral disc degeneration.

Decellularized Extracellular Matrix Containing Electrospun Fibers for Nerve Regeneration:A Comparison Between Core–Shell Structured and Preblended Composites

Advanced biomaterial-based strategies for treatment of peripheral nerve injury require precise control over both topological and biological cues for facilitating rapid and directed nerve regeneration.As a highly bioactive and tissue-specifc natural material,decellularized extracellular matrix(dECM)derived from peripheral nerves(decellularized nerve matrix,DNM)has drawn increasing attention in the feld of regenerative medicine,due to its outstanding capabilities in facilitating neurite outgrowth and remyelination.To induce and maintain sufcient topological guidance,electrospinning was conducted for fabrication of axially aligned nanofbers consisting of DNM and poly(ε-caprolactone)(PCL).Core–shell structured fbers were prepared by coaxial electrospinning using DNM as the shell and PCL as the core.Compared to the aligned electrospun fbers using preblended DNM/PCL,the core–shell structured fbers exhibited lower tensile strength,faster degradation,but considerable toughness for nerve guidance conduit preparation and relatively intact fbrous structure after long-term degradation.More importantly,the full DNM surface coverage of the aligned core–shell fbers efectively promoted axonal extension and Schwann cells migration.The DNM contents further triggered neurite bundling and myelin formation toward nerve fber maturation and functionalization.Herein,we not only pursue a multi-functional scafold design for nerve regeneration,a detailed comparison between core–shell structured and preblended electrospinning of DNM/PCL composites was also provided as an applicable paradigm for advanced tissue-engineered strategies using dECM-based biomaterials.

Corrigendum to‘Decellularized disc hydrogels for hBMSC tissue-specific differentiation and tissue regeneration’[Bioactive Materials 6(2021)3541-3556]

The authors regret missing out the below change in the acknowledgment section of the article.The original sentence reads as"This work was supported by the Major Research Plan of National Natural Science Foundation of China[No.91649204],the National Key Research and Development Program of China[2016YFC1100100],…"and the same has been corrected to"This work was supported by the National Key Research and Development Program of China[2016YFC1100100],the Major Research Plan of National Natural Science Foundation of China[No.91649204],…"and the same has been corrected to"This work was supported by the National Key Research and Development Program of China[2016YFC1100100],the Major Research Plan of National Natural Science Foundation of China[No.91649204],…".