Personalized Hydrogels for Engineering Diverse Fully Autologous Tissue Implants

Despite incremental improvements in the field of tissue engineering, no technology is currently available for producing completely autologous implants where both the cells and the scaffolding material are generated from the patient, and thus do not provoke an immune response that may lead to implant rejection. Here, a new approach is introduced to efficiently engineer any tissue type, which its differentiation cues are known, from one small tissue biopsy. Pieces of omental tissues are extracted from patients and, while the cells are reprogrammed to become induced pluripotent stem cells, the extracellular matrix is processed into an immunologically matching, thermoresponsive hydrogel. Efficient cell differentiation within a large 3D hydrogel is reported, and, as a proof of concept, the generation of functional cardiac, cortical, spinal cord, and adipogenic tissue implants is demonstrated. This versatile bioengineering approach may assist to regenerate any tissue and organ with a minimal risk for immune rejection.

[1]  J. Hunt,et al.  The innate oxygen dependant immune pathway as a sensitive parameter to predict the performance of biological graft materials. , 2012, Biomaterials.

[2]  E. Cozzi,et al.  The immunological barriers to xenotransplantation. , 2015, Tissue antigens.

[3]  Gordana Vunjak-Novakovic,et al.  Advanced maturation of human cardiac tissue grown from pluripotent stem cells , 2018, Nature.

[4]  J. K. Leach,et al.  Human mesenchymal stem cell spheroids in fibrin hydrogels exhibit improved cell survival and potential for bone healing , 2014, Cell and Tissue Research.

[5]  D. Peer,et al.  Systemic Leukocyte-Directed siRNA Delivery Revealing Cyclin D1 as an Anti-Inflammatory Target , 2008, Science.

[6]  H. Zaha,et al.  Laparoscopically harvested omental flap: results for 96 patients , 2009, Surgical Endoscopy.

[7]  R. Mahla.  Stem Cells Applications in Regenerative Medicine and Disease Therapeutics , 2016, International journal of cell biology.

[8]  K. Bendixen,et al.  Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue , 2009, Proceedings of the National Academy of Sciences.

[9]  P. Itsykson,et al.  Derivation, propagation and controlled differentiation of human embryonic stem cells in suspension , 2010, Nature Biotechnology.

[10]  Elaine L. Shelton,et al.  Omental grafting: a cell‐based therapy for blood vessel repair , 2013, Journal of tissue engineering and regenerative medicine.

[11]  D. Peer,et al.  ECM‐based macroporous sponges release essential factors to support the growth of hematopoietic cells , 2017, Journal of controlled release : official journal of the Controlled Release Society.

[12]  Ovijit Chaudhuri,et al.  Maintenance of Neural Progenitor Cell Stemness in 3D Hydrogels Requires Matrix Remodeling , 2017, Nature materials.

[13]  M. Barczewska,et al.  Therapeutic Potential of Olfactory Ensheathing Cells and Mesenchymal Stem Cells in Spinal Cord Injuries , 2017, Stem cells international.

[14]  Shunichi Homma,et al.  Composite scaffold provides a cell delivery platform for cardiovascular repair , 2011, Proceedings of the National Academy of Sciences.

[15]  Milica Radisic,et al.  Challenges in cardiac tissue engineering. , 2010, Tissue engineering. Part B, Reviews.

[16]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[17]  Sean P. Palecek,et al.  Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling , 2012, Proceedings of the National Academy of Sciences.

[18]  L. Nagy,et al.  Highly efficient differentiation of embryonic stem cells into adipocytes by ascorbic acid. , 2014, Stem cell research.

[19]  J. Rosenblatt,et al.  Dynamic rheological studies of hydrophobic interactions in injectable collagen biomaterials , 1993 .

[20]  Stephen F Badylak,et al.  Extracellular matrix as an inductive scaffold for functional tissue reconstruction. , 2014, Translational research : the journal of laboratory and clinical medicine.

[21]  Milica Radisic,et al.  A peptide-modified chitosan-collagen hydrogel for cardiac cell culture and delivery. , 2012, Acta biomaterialia.

[22]  J. Lahann,et al.  EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS Concise Review: The Evolution of Human Pluripotent Stem Cell Culture: From Feeder Cells to Synthetic Coatings , 2012 .

[23]  N. Benvenisty,et al.  Pluripotent stem cells in disease modelling and drug discovery , 2016, Nature Reviews Molecular Cell Biology.

[24]  J. D. Macklis,et al.  Modeling ALS with motor neurons derived from human induced pluripotent stem cells , 2016, Nature Neuroscience.

[25]  Shingo Hori,et al.  Generation of kidney tubular organoids from human pluripotent stem cells , 2016, Scientific Reports.

[26]  L. Looijenga,et al.  Lessons from human teratomas to guide development of safe stem cell therapies , 2012, Nature Biotechnology.

[27]  Gideon Rechavi,et al.  Analysing human neural stem cell ontogeny by consecutive isolation of Notch active neural progenitors , 2015, Nature Communications.

[28]  S. Shohet,et al.  Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. , 1988, The Journal of biological chemistry.

[29]  Tal Dvir,et al.  Nanotechnological strategies for engineering complex tissues. , 2020, Nature nanotechnology.

[30]  Michael V Sefton,et al.  Cell and biomolecule delivery for tissue repair and regeneration in the central nervous system. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[31]  Deng-Cheng Liu,et al.  Comparison of physical-chemical properties of type I collagen from different species , 2006 .

[32]  A. Eldar-Boock,et al.  Near-Infrared Dioxetane Luminophores with Direct Chemiluminescence Emission Mode. , 2017, Journal of the American Chemical Society.

[33]  Tal Dvir,et al.  Prevascularization of cardiac patch on the omentum improves its therapeutic outcome , 2009, Proceedings of the National Academy of Sciences.

[34]  H. Blau,et al.  Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation , 2017, Proceedings of the National Academy of Sciences.

[35]  J. Lieberman,et al.  Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1 , 2007, Proceedings of the National Academy of Sciences.

[36]  H. Okano,et al.  Rapid, efficient, and simple motor neuron differentiation from human pluripotent stem cells , 2015, Molecular Brain.

[37]  A. Kurtz,et al.  Recent Trends in Research with Human Pluripotent Stem Cells: Impact of Research and Use of Cell Lines in Experimental Research and Clinical Trials , 2018, Stem cell reports.

[38]  Madeline A. Lancaster,et al.  Cerebral organoids model human brain development and microcephaly , 2013, Nature.

[39]  Stephen F Badylak,et al.  Immune response to biologic scaffold materials. , 2008, Seminars in Immunology.

[40]  K. Leong,et al.  Scaffolding in tissue engineering: general approaches and tissue-specific considerations , 2008, European Spine Journal.

[41]  P. de Coppi,et al.  The Host Immune Response to Tissue-Engineered Organs: Current Problems and Future Directions. , 2016, Tissue engineering. Part B, Reviews.

[42]  H. Reichenspurner,et al.  Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells , 2016, Science Translational Medicine.

[43]  I. Yannas,et al.  Antigenicity and immunogenicity of collagen. , 2004, Journal of biomedical materials research. Part B, Applied biomaterials.

[44]  Yi Hong,et al.  Establishing Early Functional Perfusion and Structure in Tissue Engineered Cardiac Constructs. , 2015, Critical reviews in biomedical engineering.

[45]  Tobias Heckel,et al.  Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells , 2015, Nature Cell Biology.

[46]  E. Holler,et al.  Graft-versus-host disease , 2009, The Lancet.

[47]  T. Dvir,et al.  Omentum ECM-based hydrogel as a platform for cardiac cell delivery , 2015, Biomedical materials.