Heparinized chitosan stabilizes the bioactivity of BMP-2 and potentiates the osteogenic efficacy of demineralized bone matrix

Kim, Soyon; Fan, Jiabing; Lee, Chung-Sung; Chen, Chen; Bubukina, Ksenia; Lee, Min

doi:10.1186/s13036-020-0231-y

Cited by 24 publications

(23 citation statements)

References 45 publications

(52 reference statements)

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“…A recent study demonstrated that the use of DBM in combination with polymeric carriers could withhold, stabilize, and protect BMPs, resulting in the enhanced osteoinductivity. 29 In this study, a new hydrogel−siRNA conjugate is developed to enhance osteogenesis by guiding gene silencing and upregulating BMP signaling. The strategy to design a bioactive hydrogel was implemented by a two-step functionalization of methacrylate and sulfonate moieties.…”

Section: Introductionmentioning

confidence: 99%

Sulfonate Hydrogel–siRNA Conjugate Facilitates Osteogenic Differentiation of Mesenchymal Stem Cells by Controlled Gene Silencing and Activation of BMP Signaling

Kim

Fan

Lee

et al. 2021

ACS Appl. Bio Mater.

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Hydrogels have been widely used in bone tissue engineering due to their tunable characteristics that allow facile modifications with various biochemical properties to support cell growth and guide proper cell functions. Herein, we report the design of hydrogel−siRNA conjugate that facilitates osteogenesis via gene silencing and activation of bone morphogenetic protein (BMP) signaling. A sulfonate hydrogel is prepared by modifying chitosan with sulfoacetic acid to mimic a natural sulfated polysaccharide and to provide a hydrogel surface that enables BMP binding. Then, siRNA targeting noggin, an endogenous extracellular antagonist of BMP signaling, is covalently conjugated to the sulfonate hydrogel by visible blue light cross-linking. The sulfonate hydrogel−siRNA conjugate is efficient to bind BMPs and also successfully prolongs the release of siRNA for sustained noggin suppression, thereby resulting in significantly increased osteogenic differentiation. Finally, demineralized bone matrix (DBM) is incorporated into the sulfonate hydrogel−siRNA conjugate, wherein the DBM incorporation induces noggin expression via a negative feedback mechanism that regulates BMP signaling in DBM. However, the simultaneous delivery of siRNA downregulates noggin, thus facilitating endogenous BMP activity and enhancing the osteogenic efficacy of DBM. These findings support a promising hydrogel RNA silencing platform for bone tissue engineering applications.

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Section: Introductionmentioning

confidence: 99%

Sulfonate Hydrogel–siRNA Conjugate Facilitates Osteogenic Differentiation of Mesenchymal Stem Cells by Controlled Gene Silencing and Activation of BMP Signaling

Kim

Fan

Lee

et al. 2021

ACS Appl. Bio Mater.

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“…Heparinized chitosan has a protective effect on BMP bioactivity and can resist the physiological stressors related to fracture healing. It enhanced osteogenesis by inhibiting Noggin activity and attracted BMSCs ( Kim et al, 2020 ). Moreover, it exhibited synergetic effects between BMP-2 and VEGF, which effectively augmented bone formation stimulating osteogenesis and angiogenesis ( Zhang S et al, 2019 ).…”

Section: Application Of Heparin For Orthopedic Biomaterials Designmentioning

confidence: 99%

The Auxiliary Role of Heparin in Bone Regeneration and its Application in Bone Substitute Materials

Wang

Xiao

Wang

et al. 2022

Front. Bioeng. Biotechnol.

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Bone regeneration in large segmental defects depends on the action of osteoblasts and the ingrowth of new blood vessels. Therefore, it is important to promote the release of osteogenic/angiogenic growth factors. Since the discovery of heparin, its anticoagulant, anti-inflammatory, and anticancer functions have been extensively studied for over a century. Although the application of heparin is widely used in the orthopedic field, its auxiliary effect on bone regeneration is yet to be unveiled. Specifically, approximately one-third of the transforming growth factor (TGF) superfamily is bound to heparin and heparan sulfate, among which TGF-β1, TGF-β2, and bone morphogenetic protein (BMP) are the most common growth factors used. In addition, heparin can also improve the delivery and retention of BMP-2 in vivo promoting the healing of large bone defects at hyper physiological doses. In blood vessel formation, heparin still plays an integral part of fracture healing by cooperating with the platelet-derived growth factor (PDGF). Importantly, since heparin binds to growth factors and release components in nanomaterials, it can significantly facilitate the controlled release and retention of growth factors [such as fibroblast growth factor (FGF), BMP, and PDGF] in vivo. Consequently, the knowledge of scaffolds or delivery systems composed of heparin and different biomaterials (including organic, inorganic, metal, and natural polymers) is vital for material-guided bone regeneration research. This study systematically reviews the structural properties and auxiliary functions of heparin, with an emphasis on bone regeneration and its application in biomaterials under physiological conditions.

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“…Heparin, chondroitin sulfate, and hyaluronic acid are GAGs that bind GFs and have been used for sustained release to improve tissue regeneration. Heparin is a highly sulfated, negatively charged polysaccharide that forms a stable complex with GFs through specific binding domains and electrostatic interactions and has been shown to enhance GF activity. , Various substrates have been functionalized with heparin to sequester GFs for bone, ,− cartilage, ,− and osteochondral repair. − BMP-2 loaded heparin microparticles (HMPs) incorporated within alginate gels increased BMP-2 retention and resulted in robust local bone formation in critical-sized femoral defects (Figure A,B) . Similarly, heparin covalently conjugated to a hyaluronan hydrogel led to a sustained release of TGF-β1 and significantly enhanced the chondrogenic behavior of encapsulated human chondroprogenitor cells (Figure C,D) .…”

Section: Noncovalent Techniquesmentioning

confidence: 99%

Strategies to Control or Mimic Growth Factor Activity for Bone, Cartilage, and Osteochondral Tissue Engineering

2021

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Growth factors play a critical role in tissue repair and regeneration. However, their clinical success is limited by their low stability, short half-life, and rapid diffusion from the delivery site. Supraphysiological growth factor concentrations are often required to demonstrate efficacy but can lead to adverse reactions, such as inflammatory complications and increased cancer risk. These issues have motivated the development of delivery systems that enable sustained release and controlled presentation of growth factors. This review specifically focuses on bioconjugation strategies to enhance growth factor activity for bone, cartilage, and osteochondral applications. We describe approaches to localize growth factors using noncovalent and covalent methods, bind growth factors via peptides, and mimic growth factor function with mimetic peptide sequences. We also discuss emerging and future directions to control spatiotemporal growth factor delivery to improve functional tissue repair and regeneration.

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Heparinized chitosan stabilizes the bioactivity of BMP-2 and potentiates the osteogenic efficacy of demineralized bone matrix

Cited by 24 publications

References 45 publications

Sulfonate Hydrogel–siRNA Conjugate Facilitates Osteogenic Differentiation of Mesenchymal Stem Cells by Controlled Gene Silencing and Activation of BMP Signaling

Sulfonate Hydrogel–siRNA Conjugate Facilitates Osteogenic Differentiation of Mesenchymal Stem Cells by Controlled Gene Silencing and Activation of BMP Signaling

The Auxiliary Role of Heparin in Bone Regeneration and its Application in Bone Substitute Materials

Strategies to Control or Mimic Growth Factor Activity for Bone, Cartilage, and Osteochondral Tissue Engineering

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