A thermoresponsive, citrate-based macromolecule for bone regenerative engineering (original) (raw)
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Injectable In Situ –Forming pH/Thermo-Sensitive Hydrogel for Bone Tissue Engineering
Tissue Engineering Part A, 2009
We developed a novel pH-and thermo-sensitive hydrogel as a scaffold for autologous bone tissue engineering. We synthesized this polymer by adding pH-sensitive sulfamethazine oligomers (SMOs) to both ends of a thermo-sensitive poly(e-caprolactone-co-lactide)-poly(ethylene glycol)-poly(e-caprolactone-co-lactide) (PCLA-PEG-PCLA) block copolymer, yielding a pH=thermo-sensitive SMO-PCLA-PEG-PCLA-SMO block copolymer. The synthesized block copolymer solution rapidly formed a stable gel under physiological conditions (pH 7.4 and 378C), whereas it formed a sol at pH 8.0 and 378C, making it injectable. This pH=thermo-sensitive hydrogel exhibited high biocompatibility in a Dulbecco's modified Eagle's medium extract test. Under physiological conditions, the hydrogel easily encapsulated human mesenchymal stem cells (hMSCs) and recombinant human bone morphogenetic protein-2 (rhBMP-2), with encapsulating efficiencies of about 90% and 85%, respectively. To assay for ectopic bone formation in vivo, we subcutaneously injected a polymer solution containing hMSCs and rhBMP-2 into the back of mice, after which we could observe hMSC differentiation for up to 7 weeks. Histological studies revealed mineralized tissue formation and high levels of alkaline phosphatase activity in the mineralized tissue. Therefore, this pH=thermo-sensitive SMO-PCLA-PEG-PCLA-SMO block copolymer demonstrated potential as an injectable scaffold for bone tissue engineering, with in situ formation capabilities.
Orthopaedic Proceedings, 2018
Bone loss resulting from degenerative diseases and trauma is a significant clinical burden which is likely to grow exponentially with the aging population. In a number of conditions where pre-formed materials are clinically inappropriate an injectable bone forming hydrogel could be beneficial. The development of an injectable hydrogel to stimulate bone repair and regeneration would have broad clinical impact and economic benefit in a variety of orthopedic clinical applications. We have previously reported the development of a Laponite ® crosslinked pNIPAMco-DMAc (L-pNIPAM-co-DMAc) hydrogel delivery system, loaded with hydroxyapatite nanoparticles (HAPna), which was capable of inducing osteogenic differentiation of mesenchymal stem cells (MSCs) without the need for additional growth factors in vitro. However to enable progression towards clinical acceptability, biocompatibility and efficacy of the L-pNIPAM-co-DMAc hydrogel to induce bone repair in vivo must be determined. Biocompatibility was evaluated by subcutaneous implantation for 6 weeks in rats, and efficacy to augment bone repair was evaluated within a rat femur defect model for 4 weeks. No inflammatory reactions, organ toxicity or systemic toxicity were observed. In young male rats where hydrogel was injected, defect healing was less effective than sham operated controls when rat MSCs were incorporated. Enhanced bone healing was observed however, in aged exbreeder female rats where acellular hydrogel was injected, with increased deposition of collagen type I and Runx2. Integration of the hydrogel with surrounding bone was observed without the need for delivered MSCs; native cell infiltration was also seen and bone formation was observed within all hydrogel systems investigated. This hydrogel can be delivered directly into the target site, is biocompatible, promotes increased bone formation and facilitates migration of cells to promote integration with surrounding bone, for safe and efficacious bone repair.
Oncotarget, 2018
Bone loss resulting from degenerative diseases and trauma is a significant clinical burden which is likely to grow exponentially with the aging population. In a number of conditions where pre-formed materials are clinically inappropriate an injectable bone forming hydrogel could be beneficial. The development of an injectable hydrogel to stimulate bone repair and regeneration would have broad clinical impact and economic benefit in a variety of orthopedic clinical applications. We have previously reported the development of a Laponite ® crosslinked pNIPAMco-DMAc (L-pNIPAM-co-DMAc) hydrogel delivery system, loaded with hydroxyapatite nanoparticles (HAPna), which was capable of inducing osteogenic differentiation of mesenchymal stem cells (MSCs) without the need for additional growth factors in vitro. However to enable progression towards clinical acceptability, biocompatibility and efficacy of the L-pNIPAM-co-DMAc hydrogel to induce bone repair in vivo must be determined. Biocompatibility was evaluated by subcutaneous implantation for 6 weeks in rats, and efficacy to augment bone repair was evaluated within a rat femur defect model for 4 weeks. No inflammatory reactions, organ toxicity or systemic toxicity were observed. In young male rats where hydrogel was injected, defect healing was less effective than sham operated controls when rat MSCs were incorporated. Enhanced bone healing was observed however, in aged exbreeder female rats where acellular hydrogel was injected, with increased deposition of collagen type I and Runx2. Integration of the hydrogel with surrounding bone was observed without the need for delivered MSCs; native cell infiltration was also seen and bone formation was observed within all hydrogel systems investigated. This hydrogel can be delivered directly into the target site, is biocompatible, promotes increased bone formation and facilitates migration of cells to promote integration with surrounding bone, for safe and efficacious bone repair.
Bioactive hydrogels for bone regeneration
Bioactive Materials, 2018
Bone self-healing is limited and generally requires external intervention to augment bone repair and regeneration. While traditional methods for repairing bone defects such as autografts, allografts, and xenografts have been widely used, they all have corresponding disadvantages, thus limiting their clinical use. Despite the development of a variety of biomaterials, including metal implants, calcium phosphate cements (CPC), hydroxyapatite, etc., the desired therapeutic effect is not fully achieved. Currently, polymeric scaffolds, particularly hydrogels, are of interest and their unique configurations and tunable physicochemical properties have been extensively studied. This review will focus on the applications of various cutting-edge bioactive hydrogels systems in bone regeneration, as well as their advantages and limitations. We will examine the composition and defects of the bone, discuss the current biomaterials for bone regeneration, and classify recently developed polymeric materials for hydrogel synthesis. We will also elaborate on the properties of desirable hydrogels as well as the fabrication techniques and different delivery strategies. Finally, the existing challenges, considerations, and the future prospective of hydrogels in bone regeneration will be outlined.
International Journal of Molecular Sciences
Biomaterials that promote angiogenesis are required for repair and regeneration of bone. In-situ formed injectable hydrogels functionalised with bioactive agents, facilitating angiogenesis have high demand for bone regeneration. In this study, pH and thermosensitive hydrogels based on chitosan (CS) and hydroxyapatite (HA) composite materials loaded with heparin (Hep) were investigated for their pro-angiogenic potential. Hydrogel formulations with varying Hep concentrations were prepared by sol–gel technique for these homogeneous solutions were neutralised with sodium bicarbonate (NaHCO3) at 4 °C. Solutions (CS/HA/Hep) constituted hydrogels setting at 37 °C which was initiated from surface in 5–10 minutes. Hydrogels were characterised by performing injectability, gelation, rheology, morphology, chemical and biological analyses. Hydrogel solutions facilitated manual dropwise injection from 21 Gauge which is highly used for orthopaedic and dental administrations, and the maximum inject...
Journal of Biomedical Materials Research Part A, 2013
Among the less invasive surgical procedures for tissue engineering application, injectable in situ gelling systems have gained great attention. In this contest, this article is aimed to realize thermosensitive chitosan-based hydrogels, crosslinked with b-glycerophosphate and reinforced via physical interactions with b-tricalcium phosphate. The kinetics of sol-gel transition and the composite hydrogel properties were investigated by rheological analysis. The hydrogels were also characterized by Fourier transform infrared study, X-ray diffraction, scanning electron microscopy, transmission electron microscopy analysis, and thermal and biological studies. The hydrogels exhibit a gel-phase transition at body temperature, and a threedimensional network with typical rheological properties of a strong gel. The presence of the inorganic phase, made up of nanocrystals, provides a structure with chemico-physical composition that mimics natural bone tissue, favoring cellular activity. These findings suggest the potential of the materials as promising candidates for hard tissue regeneration. V C 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A:000-000, 2013.
Oncotarget
Bone loss resulting from degenerative diseases and trauma is a significant clinical burden which is likely to grow exponentially with the aging population. In a number of conditions where pre-formed materials are clinically inappropriate an injectable bone forming hydrogel could be beneficial. The development of an injectable hydrogel to stimulate bone repair and regeneration would have broad clinical impact and economic benefit in a variety of orthopedic clinical applications. We have previously reported the development of a Laponite ® crosslinked pNIPAMco-DMAc (L-pNIPAM-co-DMAc) hydrogel delivery system, loaded with hydroxyapatite nanoparticles (HAPna), which was capable of inducing osteogenic differentiation of mesenchymal stem cells (MSCs) without the need for additional growth factors in vitro. However to enable progression towards clinical acceptability, biocompatibility and efficacy of the L-pNIPAM-co-DMAc hydrogel to induce bone repair in vivo must be determined. Biocompatibility was evaluated by subcutaneous implantation for 6 weeks in rats, and efficacy to augment bone repair was evaluated within a rat femur defect model for 4 weeks. No inflammatory reactions, organ toxicity or systemic toxicity were observed. In young male rats where hydrogel was injected, defect healing was less effective than sham operated controls when rat MSCs were incorporated. Enhanced bone healing was observed however, in aged exbreeder female rats where acellular hydrogel was injected, with increased deposition of collagen type I and Runx2. Integration of the hydrogel with surrounding bone was observed without the need for delivered MSCs; native cell infiltration was also seen and bone formation was observed within all hydrogel systems investigated. This hydrogel can be delivered directly into the target site, is biocompatible, promotes increased bone formation and facilitates migration of cells to promote integration with surrounding bone, for safe and efficacious bone repair.
Biomedical materials (Bristol, England), 2016
Successful bone tissue engineering requires at the minimum sufficient osteoblast progenitors, efficient osteoinductive factors, and biocompatible scaffolding materials. We previously demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent factors in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). Here, we investigated the potential use of a biodegradable citrate-based thermosensitive macromolecule, poly(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) mixed with gelatin (PPCNG) as a scaffold for the delivery of BMP9-stimulated MSCs to promote localized bone formation. The addition of gelatin to PPCN effectively enhanced the cell adhesion and survival properties of MSCs entrapped within the gel in 3D culture. Using the BMP9-transduced MSC line immortalized mouse embryonic fibroblasts (iMEFs), we found that PPCNG facilitated BMP9-induced osteogenic differentiation of iMEFs in vivo and promoted the formation of well-ossified and ...
ACS Omega, 2018
In this study, an injectable thermoresponsive hydroxypropyl guar-graf t-poly(N-vinylcaprolactam) (HPG-g-PNVCL) copolymer was synthesized by graft polymerization. The reaction parameters such as temperature, time, monomer, and initiator concentrations were varied. In addition, the HPG-g-PNVCL copolymer was modified with nano-hydroxyapatite (n-HA) by in situ covalent cross-linking using divinyl sulfone (DVS) cross-linker to obtain HPG-g-PNVCL/n-HA/DVS composite material. Grafted copolymer and composite materials were characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, proton nuclear magnetic resonance spectroscopy (1 H NMR), and differential scanning calorimetry. The morphology of the grafted copolymer (HPG-g-PNVCL) and the composite (HPG-g-PNVCL/ n-HA/DVS) was examined using scanning electron microscopy (SEM), which showed interconnected porous honeycomb-like structures. Using Ultraviolet−visible spectroscopy, low critical solution temperature for HPG-g-PNVCL was observed at 34°C, which is close to the rheology gel point at 33.5°C. The thermoreversibility of HPG-g-PNVCL was proved by rheological analysis. The HPG-g-PNVCL hydrogel was employed for slow release of the drug molecule. Ciprofloxacin, a commonly known antibiotic, was used for sustainable release from the HPG-g-PNVCL hydrogel as a function of time at 37°C because of viscous nature and thermogelation of the copolymer. In vitro cytotoxicity study reveals that the HPG-g-PNVCL thermogelling polymer works as a biocompatible scaffold for osteoblastic cell growth. Additionally, in vitro biomineralization study of HPG-g-PNVCL/n-HA/DVS was conducted using a simulated body fluid, and apatite-like structure formation was observed by SEM.