3D Printing of Microenvironment‐Specific Bioinspired and Exosome‐Reinforced Hydrogel Scaffolds for Efficient Cartilage and Subchondral Bone Regeneration

In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus, elucidating how spatial microenvironment-specific biomimetic scaffolds can be used to simultaneously regenerate osteochondral tissue is an important research topic. Herein, a novel bioinspired double-network hydrogel scaffold produced via 3D printing with tissue-specific decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)-derived exosomes is described. The bionic hydrogel scaffolds promote rat bone marrow MSC attachment, spread, migration, proliferation, and chondrogenic and osteogenic differentiation in vitro, as determined based on the sustained release of bioactive exosomes. Furthermore, the 3D-printed microenvironment-specific heterogeneous bilayer scaffolds efficiently accelerate the simultaneous regeneration of cartilage and subchondral bone tissues in a rat preclinical model. In conclusion, 3D dECM-based microenvironment-specific biomimetics encapsulated with bioactive exosomes can serve as a novel cell-free recipe for stem cell therapy when treating injured or degenerative joints. This strategy provides a promising platform for complex zonal tissue regeneration whilst holding attractive clinical translation potential.

[1]  Qing Jiang,et al.  Dopamine‐Integrated Nanointerface between Fibrillar Matrix and Hydrophilic Nanohydroxyapatite Regulates Immune Microenvironment to Boost Endogenous Bone Regeneration , 2023, Advanced Functional Materials.

[2]  Su Kyeom Kim,et al.  Three-dimensional heart extracellular matrix enhances chemically induced direct cardiac reprogramming , 2022, Science advances.

[3]  Wan-Ju Li,et al.  CTR9 drives osteochondral lineage differentiation of human mesenchymal stem cells via epigenetic regulation of BMP-2 signaling , 2022, Science advances.

[4]  P. Tanwar,et al.  Bovine and human endometrium-derived hydrogels support organoid culture from healthy and cancerous tissues , 2022, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Daniel J. Shiwarski,et al.  3D-bioprinted human tissue and the path toward clinical translation , 2022, Science Translational Medicine.

[6]  C. E. Meyer,et al.  Engineered Hemostatic Biomaterials for Sealing Wounds. , 2022, Chemical reviews.

[7]  Xueting Wang,et al.  Insights into the use of genetically modified decellularized biomaterials for tissue engineering and regenerative medicine. , 2022, Advanced drug delivery reviews.

[8]  U. Wyneken,et al.  Neuropilin‐1 is present on Foxp3+ T regulatory cell‐derived small extracellular vesicles and mediates immunity against skin transplantation , 2022, Journal of extracellular vesicles.

[9]  Daidi Fan,et al.  Artificial Nonenzymatic Antioxidant MXene Nanosheet-Anchored Injectable Hydrogel as a Mild Photothermal-Controlled Oxygen Release Platform for Diabetic Wound Healing. , 2022, ACS nano.

[10]  Seung‐Woo Cho,et al.  Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids , 2022, Nature communications.

[11]  P. Weiss,et al.  Material‐Assisted Strategies for Osteochondral Defect Repair , 2022, Advanced science.

[12]  C. T. Buckley,et al.  Bilayered Extracellular Matrix Derived Scaffolds with Anisotropic Pore Architecture Guide Tissue Organization During Osteochondral Defect Repair. , 2022, Acta biomaterialia.

[13]  S. Odum,et al.  Isolated Osteochondral Autograft Versus Allograft Transplantation for the Treatment of Symptomatic Cartilage Lesions of the Knee: A Systematic Review and Meta-analysis , 2022, The American journal of sports medicine.

[14]  J. Fisher,et al.  Sustained released of bioactive mesenchymal stromal cell-derived extracellular vesicles from 3D-printed gelatin methacrylate hydrogels. , 2022, Journal of biomedical materials research. Part A.

[15]  J. Lammerding,et al.  Enucleated human mesenchymal stromal cells for the homing and the delivery of therapeutic cargos in vivo , 2021, Nature Biomedical Engineering.

[16]  Seung‐Woo Cho,et al.  Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids , 2021, Nature Communications.

[17]  Zhenxing Shao,et al.  Cryo-self-assembled silk fibroin sponge as a biodegradable platform for enzyme-responsive delivery of exosomes , 2021, Bioactive materials.

[18]  Qiang Liu,et al.  Comparison of three different acidic solutions in tendon decellularized extracellular matrix bio-ink fabrication for 3D cell printing. , 2021, Acta biomaterialia.

[19]  Haifeng Chen,et al.  Mesenchymal stromal exosome–functionalized scaffolds induce innate and adaptive immunomodulatory responses toward tissue repair , 2021, Science Advances.

[20]  Z. Shao,et al.  Decellularized Disc Hydrogels for hBMSCs tissue-specific differentiation and tissue regeneration , 2021, Bioactive materials.

[21]  Xiaoqing Hu,et al.  The Tissue Origin Effect of Extracellular Vesicles on Cartilage and Bone Regeneration. , 2021, Acta biomaterialia.

[22]  Dongan Wang,et al.  Modified hyaluronic acid hydrogels with chemical groups that facilitate adhesion to host tissues enhance cartilage regeneration , 2020, Bioactive materials.

[23]  Mingying Yang,et al.  Human Mesenchymal Stem Cell Derived Exosomes Enhance Cell‐Free Bone Regeneration by Altering Their miRNAs Profiles , 2020, Advanced science.

[24]  Xin Fu,et al.  Autologous Fractionated Adipose Tissue as a Natural Biomaterial and Novel One-Step Stem Cell Therapy for Repairing Articular Cartilage Defects , 2020, Frontiers in Cell and Developmental Biology.

[25]  Jingjie Hu,et al.  Bioactive‐Tissue‐Derived Nanocomposite Hydrogel for Permanent Arterial Embolization and Enhanced Vascular Healing , 2020, Advanced materials.

[26]  Keng Lin Wong,et al.  Intra-articular injections of mesenchymal stem cell exosomes and hyaluronic acid improve structural and mechanical properties of repaired cartilage in a rabbit model. , 2020, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[27]  D. Mooney,et al.  Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration , 2020, Advanced functional materials.

[28]  Raghu Kalluri,et al.  The biology, function, and biomedical applications of exosomes , 2020, Science.

[29]  Xin Fu,et al.  Bone marrow mesenchymal stem cells-derived exosomes promote tendon regeneration via facilitating the proliferation and migration of endogenous tendon stem/progenitor cells. , 2020, Acta biomaterialia.

[30]  F. Lv,et al.  miR-23a-3p-abundant small extracellular vesicles released from Gelma/nanoclay hydrogel for cartilage regeneration , 2020, Journal of extracellular vesicles.

[31]  A. Dietz,et al.  Sustained perfusion of revascularized bioengineered livers heterotopically transplanted into immunosuppressed pigs , 2019, Nature Biomedical Engineering.

[32]  J. Karp,et al.  The Kinetics of Small Extracellular Vesicle Delivery Impacts Skin Tissue Regeneration. , 2019, ACS nano.

[33]  Jerry C. Hu,et al.  Surgical and tissue engineering strategies for articular cartilage and meniscus repair , 2019, Nature Reviews Rheumatology.

[34]  Changshun Ruan,et al.  Osteochondral Regeneration with 3D‐Printed Biodegradable High‐Strength Supramolecular Polymer Reinforced‐Gelatin Hydrogel Scaffolds , 2019, Advanced science.

[35]  S. Vakhrushev,et al.  Different isolation approaches lead to diverse glycosylated extracellular vesicle populations , 2019, Journal of extracellular vesicles.

[36]  shanliang song,et al.  Biomimetic Composite Scaffolds to Manipulate Stem Cells for Aiding Rheumatoid Arthritis Management , 2019, Advanced Functional Materials.

[37]  S. Fan,et al.  Desktop-stereolithography 3D printing of a radially oriented extracellular matrix/mesenchymal stem cell exosome bioink for osteochondral defect regeneration , 2019, Theranostics.

[38]  W. Grayson,et al.  Heparin‐Conjugated Decellularized Bone Particles Promote Enhanced Osteogenic Signaling of PDGF‐BB to Adipose‐Derived Stem Cells in Tissue Engineered Bone Grafts , 2019, Advanced healthcare materials.

[39]  Liu Yang,et al.  miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. , 2019, Biomaterials.

[40]  S. Paek,et al.  A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy , 2019, Nature Biomedical Engineering.

[41]  Baolin Guo,et al.  Adhesive Hemostatic Conducting Injectable Composite Hydrogels with Sustained Drug Release and Photothermal Antibacterial Activity to Promote Full-Thickness Skin Regeneration During Wound Healing. , 2019, Small.

[42]  Lei Chen,et al.  3D printing of a lithium-calcium-silicate crystal bioscaffold with dual bioactivities for osteochondral interface reconstruction. , 2019, Biomaterials.

[43]  S. Lim,et al.  MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. , 2019, Biomaterials.

[44]  Eamon J. Sheehy,et al.  Tissue-specific extracellular matrix scaffolds for the regeneration of spatially complex musculoskeletal tissues. , 2019, Biomaterials.

[45]  Qingqiang Yao,et al.  3D Molecularly Functionalized Cell‐Free Biomimetic Scaffolds for Osteochondral Regeneration , 2018, Advanced Functional Materials.

[46]  B. Gulyás,et al.  Lineage-specific exosomes could override extracellular matrix mediated human mesenchymal stem cell differentiation. , 2018, Biomaterials.

[47]  Jianlin Shi,et al.  Exosome Biochemistry and Advanced Nanotechnology for Next‐Generation Theranostic Platforms , 2018, Advanced materials.

[48]  May Win Naing,et al.  Organ-Derived Decellularized Extracellular Matrix: A Game Changer for Bioink Manufacturing? , 2018, Trends in biotechnology.

[49]  Hui-zhen Jia,et al.  NIR‐Activated Polydopamine‐Coated Carrier‐Free “Nanobomb” for In Situ On‐Demand Drug Release , 2018, Advanced science.

[50]  S. Lim,et al.  MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. , 2018, Biomaterials.

[51]  Adam E Jakus,et al.  “Tissue Papers” from Organ‐Specific Decellularized Extracellular Matrices , 2017, Advanced functional materials.

[52]  Xin Fu,et al.  Structurally and Functionally Optimized Silk‐Fibroin–Gelatin Scaffold Using 3D Printing to Repair Cartilage Injury In Vitro and In Vivo , 2017, Advanced materials.

[53]  Xin Fu,et al.  Microfracture combined with functional pig peritoneum-derived acellular matrix for cartilage repair in rabbit models. , 2017, Acta biomaterialia.

[54]  Benjamin B. Rothrauff,et al.  Region-Specific Effect of the Decellularized Meniscus Extracellular Matrix on Mesenchymal Stem Cell–Based Meniscus Tissue Engineering , 2017, The American journal of sports medicine.

[55]  S. Lim,et al.  Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. , 2016, Osteoarthritis and cartilage.

[56]  Xin Zhang,et al.  Transplantation of allogenic chondrocytes with chitosan hydrogel-demineralized bone matrix hybrid scaffold to repair rabbit cartilage injury. , 2016, Biomaterials.

[57]  T. Ogura,et al.  Tissue-Specific Progenitor and Stem Cells Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model , 2016 .

[58]  Deok‐Ho Kim,et al.  Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink , 2014, Nature Communications.

[59]  Xin Zhang,et al.  One-Step Repair for Cartilage Defects in a Rabbit Model , 2014, The American journal of sports medicine.

[60]  Louis Casteilla,et al.  Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). , 2013, Cytotherapy.

[61]  B. Min,et al.  Using Cartilage Extracellular Matrix (CECM) Membrane to Enhance the Reparability of the Bone Marrow Stimulation Technique for Articular Cartilage Defect in Canine Model , 2012 .

[62]  Stephen F Badylak,et al.  An overview of tissue and whole organ decellularization processes. , 2011, Biomaterials.

[63]  Joshua D. Harris,et al.  The effects of lesion size and location on subchondral bone contact in experimental knee articular cartilage defects in a bovine model. , 2010, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[64]  Xin Zhang,et al.  Surface modification on polycaprolactone electrospun mesh and human decalcified bone scaffold with synovium-derived mesenchymal stem cells-affinity peptide for tissue engineering. , 2015, Journal of biomedical materials research. Part A.

[65]  Fergal J O'Brien,et al.  The effect of mean pore size on cell attachment, proliferation and migration in collagen-glycosaminoglycan scaffolds for bone tissue engineering. , 2010, Biomaterials.