title: Sulfated hyaluronic acid hydrogels with retarded degradation and enhanced growth factor retention promote hMSC chondrogenesis and articular cartilage integrity with reduced hypertrophy.
abstract: Recently, hyaluronic acid (HA) hydrogels have been extensively researched for delivering cells and drugs to repair damaged tissues, particularly articular cartilage. However, the in vivo degradation of HA is fast, thus limiting the clinical translation of HA hydrogels. Furthermore, HA cannot bind proteins with high affinity because of the lack of negatively charged sulfate groups. In this study, we conjugated tunable amount of sulfate groups to HA. The sulfated HA exhibits significantly slower degradation by hyaluronidase compared to the wild type HA. We hypothesize that the sulfation reduces the available HA octasaccharide substrate needed for the effective catalytic action of hyaluronidase. Moreover, the sulfated HA hydrogels significantly improve the protein sequestration, thereby effectively extending the availability of the proteinaceous drugs in the hydrogels. In the following in vitro study, we demonstrate that the HA hydrogel sulfation exerts no negative effect on the viability of encapsulated human mesenchymal stem cells (hMSCs). Furthermore, the sulfated HA hydrogels promote the chondrogenesis and suppresses the hypertrophy of encapsulated hMSCs both in vitro and in vivo. Moreover, intra-articular injections of the sulfated HA hydrogels avert the cartilage abrasion and hypertrophy in the animal osteoarthritic joints. Collectively, our findings demonstrate that the sulfated HA is a promising biomaterial for the delivery of therapeutic agents to aid the regeneration of injured or diseased tissues and organs.
  
  
  
  In this paper, we conjugated sulfate groups to hyaluronic acid (HA) and demonstrated the slow degradation and growth factor delivery of sulfated HA. Furthermore, the in vitro and in vivo culture of hMSCs laden HA hydrogels proved that the sulfation of HA hydrogels not only promotes the chondrogenesis of hMSCs but also suppresses hypertrophic differentiation of the chondrogenically induced hMSCs. The animal OA model study showed that the injected sulfated HA hydrogels significantly reduced the cartilage abrasion and hypertrophy in the animal OA joints. We believe that this study will provide important insights into the design and optimization of the HA-based hydrogels as the scaffold materials for cartilage regeneration and OA treatment in clinical setting.
authors.affiliation: Division of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong.
authors.forename: Qian
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Division of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Department of Orthopaedic and Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, New Territories, 999077, Hong Kong.
authors.forename: Sien
authors.initials: S
authors.lastname: Lin
authors.affiliation: Division of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong.
authors.forename: Kunyu
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Division of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong.
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Dong
authors.affiliation: Division of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Department of Orthopaedic and Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, New Territories, 999077, Hong Kong.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wu
authors.affiliation: Division of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong.
authors.forename: Heqin
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic and Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, New Territories, 999077, Hong Kong.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Division of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Shun Hing Institute of Advanced Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong; Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, PR China; Centre for Novel Biomaterials, The Chinese University of Hong Kong, Shatin, New Territories, 999077, Hong Kong. Electronic address: lbian@mae.cuhk.edu.hk.
authors.forename: Liming
authors.initials: L
authors.lastname: Bian
mesh_terms: D065966:Absorption, Physicochemical; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects / Q000502:physiology*; D003131:Combined Modality Therapy / Q000295:instrumentation / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D004058:Diffusion; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D006984:Hypertrophy / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000295:instrumentation* / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020370:Osteoarthritis, Knee / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013431:Sulfates / Q000737:chemistry; D054457:Tissue Scaffolds; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D036341:Intercellular Signaling Peptides and Proteins; D013431:Sulfates; D006820:Hyaluronic Acid
keywords: Chondrogenesis; Degradation; Hyaluronic acid; Hypertrophy; Sulfation