Modular extracellular matrices: solutions for the puzzle.

The common technique of growing cells in two-dimensions (2-D) is gradually being replaced by culturing cells on matrices with more appropriate composition and stiffness, or by encapsulation of cells in three-dimensions (3-D). The universal acceptance of the new 3-D paradigm has been constrained by the absence of a commercially available, biocompatible material that offers ease of use, experimental flexibility, and a seamless transition from in vitro to in vivo applications. The challenge-the puzzle that needs a solution-is to replicate the complexity of the native extracellular matrix (ECM) environment with the minimum number of components necessary to allow cells to rebuild and replicate a given tissue. For use in drug discovery, toxicology, cell banking, and ultimately in reparative medicine, the ideal matrix would therefore need to be highly reproducible, manufacturable, approvable, and affordable. Herein we describe the development of a set of modular components that can be assembled into biomimetic materials that meet these requirements. These semi-synthetic ECMs, or sECMs, are based on hyaluronan derivatives that form covalently crosslinked, biodegradable hydrogels suitable for 3-D culture of primary and stem cells in vitro, and for tissue formation in vivo. The sECMs can be engineered to provide appropriate biological cues needed to recapitulate the complexity of a given ECM environment. Specific applications for different sECM compositions include stem cell expansion with control of differentiation, scar-free wound healing, growth factor delivery, cell delivery for osteochondral defect and liver repair, and development of vascularized tumor xenografts for personalized chemotherapy.

[1]  Glenn D Prestwich,et al.  Structural Variations in a Single Hyaluronan Derivative Significantly Alter Wound‐Healing Effects in the Rabbit Maxillary Sinus , 2007, The Laryngoscope.

[2]  Glenn D Prestwich,et al.  Synthesis of hyaluronan haloacetates and biology of novel cross-linker-free synthetic extracellular matrix hydrogels. , 2007, Biomacromolecules.

[3]  I. Mian,et al.  Tissue architecture: the ultimate regulator of breast epithelial function. , 2003, Current opinion in cell biology.

[4]  Glenn D. Prestwich,et al.  In Vivo Engineering of the Vocal Fold Extracellular Matrix with Injectable Hyaluronic Acid Hydrogels: Early Effects on Tissue Repair and Biomechanics in a Rabbit Model , 2005, The Annals of otology, rhinology, and laryngology.

[5]  Glenn D Prestwich,et al.  Synthesis and evaluation of injectable, in situ crosslinkable synthetic extracellular matrices for tissue engineering. , 2006, Journal of biomedical materials research. Part A.

[6]  Fabio Palumbo,et al.  Disulfide-crosslinked hyaluronan-gelatin hydrogel films: a covalent mimic of the extracellular matrix for in vitro cell growth. , 2003, Biomaterials.

[7]  Glenn D Prestwich,et al.  Simplifying the extracellular matrix for 3‐D cell culture and tissue engineering: A pragmatic approach , 2007, Journal of cellular biochemistry.

[8]  Glenn D Prestwich,et al.  Crosslinked hydrogels for tympanic membrane repair , 2006, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[9]  Robert J Fisher,et al.  Heparin-regulated release of growth factors in vitro and angiogenic response in vivo to implanted hyaluronan hydrogels containing VEGF and bFGF. , 2006, Biomaterials.

[10]  Glenn D Prestwich,et al.  Postoperative pericardial adhesion prevention using Carbylan-SX in a rabbit model. , 2007, The Journal of surgical research.

[11]  Glenn D Prestwich,et al.  Cross-Linked Hyaluronan-Coated Stents in the Prevention of Airway Stenosis , 2006, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[12]  Sara Ellis Simonsen,et al.  Cross-Linked Hydrogels for Middle Ear Packing , 2006, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[13]  Glenn D Prestwich,et al.  In situ crosslinkable hyaluronan hydrogels for tissue engineering. , 2004, Biomaterials.

[14]  Glenn D Prestwich,et al.  Injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor. , 2005, Biomaterials.

[15]  J. Fraser,et al.  Hyaluronan: its nature, distribution, functions and turnover , 1997, Journal of internal medicine.

[16]  Andrew A. Pitsillides,et al.  An Essential Role for the Interaction Between Hyaluronan and Hyaluronan Binding Proteins During Joint Development , 1998, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[17]  M J Bissell,et al.  Microenvironmental Regulators of Tissue Structure and Function Also Regulate Tumor Induction and Progression : The Role of Extracellular Matrix and Its Degrading Enzymes , 2022 .

[18]  Glenn D Prestwich,et al.  Reduced postoperative intra-abdominal adhesions using Carbylan-SX, a semisynthetic glycosaminoglycan hydrogel. , 2007, Fertility and sterility.

[19]  B. Toole,et al.  Hyaluronan in morphogenesis , 1997, Seminars in cell & developmental biology.

[20]  Glenn D Prestwich,et al.  Molecular stenting with a crosslinked hyaluronan derivative inhibits collagen gel contraction. , 2006, The Journal of investigative dermatology.

[21]  Glenn D Prestwich,et al.  Accelerated repair of cortical bone defects using a synthetic extracellular matrix to deliver human demineralized bone matrix , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[22]  Glenn D Prestwich,et al.  Evaluating drug efficacy and toxicology in three dimensions: using synthetic extracellular matrices in drug discovery. , 2008, Accounts of chemical research.

[23]  Glenn D Prestwich,et al.  Attachment and spreading of fibroblasts on an RGD peptide-modified injectable hyaluronan hydrogel. , 2004, Journal of biomedical materials research. Part A.

[24]  E. Turley,et al.  Rapid hyaluronan uptake is associated with enhanced motility: implications for an intracellular mode of action , 1998, FEBS letters.

[25]  Glenn D Prestwich,et al.  Adipose tissue engineering with naturally derived scaffolds and adipose-derived stem cells. , 2007, Biomaterials.

[26]  J M Davidson,et al.  Hyaluronate derivatives and their application to wound healing: preliminary observations. , 1991, Clinical materials.

[27]  G. Laurie,et al.  Basement membrane complexes with biological activity. , 1986, Biochemistry.

[28]  Michael S. Goldberg,et al.  Nanostructured materials for applications in drug delivery and tissue engineering , 2007, Journal of biomaterials science. Polymer edition.

[29]  D. Nance,et al.  Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility [published erratum appears in J Cell Biol 1992 Aug;118(3):753] , 1992, The Journal of cell biology.

[30]  Charles A. Hales,et al.  Chemistry and biology of hyaluronan , 2004 .

[31]  Glenn D Prestwich,et al.  Synthesis and characterization of novel thiol-reactive poly(ethylene glycol) cross-linkers for extracellular-matrix-mimetic biomaterials. , 2007, Biomacromolecules.

[32]  B. Gerdin,et al.  Dynamic role of hyaluronan (HYA) in connective tissue activation and inflammation , 1997, Journal of internal medicine.

[33]  Glenn D Prestwich,et al.  Tumor engineering: orthotopic cancer models in mice using cell-loaded, injectable, cross-linked hyaluronan-derived hydrogels. , 2007, Tissue engineering.

[34]  Glenn D Prestwich,et al.  Injectable synthetic extracellular matrices for tissue engineering and repair. , 2006, Advances in experimental medicine and biology.

[35]  Glenn D Prestwich,et al.  Release of basic fibroblast growth factor from a crosslinked glycosaminoglycan hydrogel promotes wound healing , 2007, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[36]  Glenn D Prestwich,et al.  Vocal fold tissue repair in vivo using a synthetic extracellular matrix. , 2006, Tissue engineering.

[37]  Glenn D Prestwich,et al.  Osteochondral defect repair with autologous bone marrow-derived mesenchymal stem cells in an injectable, in situ, cross-linked synthetic extracellular matrix. , 2006, Tissue engineering.

[38]  D. Monti,et al.  Mucoadhesive ophthalmic vehicles: evaluation of polymeric low-viscosity formulations. , 1994, Journal of ocular pharmacology.

[39]  G. Prestwich,et al.  Effect of a synthetic extracellular matrix on vocal fold lamina propria gene expression in early wound healing. , 2006, Tissue engineering.

[40]  Glenn D Prestwich,et al.  Disulfide cross-linked hyaluronan hydrogels. , 2002, Biomacromolecules.

[41]  L. Cima,et al.  Polymer substrates for controlled biological interactions , 1994, Journal of cellular biochemistry.

[42]  Jack Lombardi,et al.  Rheological characterization of in situ cross-linkable hyaluronan hydrogels. , 2005, Biomacromolecules.

[43]  Glenn D Prestwich,et al.  Fibronectin functional domains coupled to hyaluronan stimulate adult human dermal fibroblast responses critical for wound healing. , 2006, Tissue engineering.