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author:("Kim, jinkui")
1.  Adipose-Derived Stem Cells and BMP-2 Delivery in Chitosan-Based 3D Constructs to Enhance Bone Regeneration in a Rat Mandibular Defect Model 
Tissue Engineering. Part A  2014;20(15-16):2169-2179.
Reconstructing segmental mandiblular defects remains a challenge in the clinic. Tissue engineering strategies provide an alternative option to resolve this problem. The objective of the present study was to determine the effects of adipose-derived stem cells (ASCs) and bone morphogenetic proteins-2 (BMP-2) in three-dimensional (3D) scaffolds on mandibular repair in a small animal model. Noggin expression levels in ASCs were downregulated by a lentiviral short hairpin RNA strategy to enhance ASC osteogenesis (ASCsNog−). Chitosan (CH) and chondroitin sulfate (CS), natural polysaccharides, were fabricated into 3D porous scaffolds, which were further modified with apatite coatings for enhanced cellular responses and efficient delivery of BMP-2. The efficacy of 3D apatite-coated CH/CS scaffolds supplemented with ASCsNog− and BMP-2 were evaluated in a rat critical-sized mandibular defect model. After 8 weeks postimplantation, the scaffolds treated with ASCsNog− and BMP-2 significantly promoted rat mandibular regeneration as demonstrated by micro-computerized tomography, histology, and immunohistochemistry, compared with the groups treated with ASCsNog− or BMP-2 alone. These results suggest that our combinatorial strategy of ASCsNog−+BMP-2 in 3D apatite microenvironments can significantly promote mandibular regeneration, and these may provide a potential tissue engineering approach to repair large bony defects.
PMCID: PMC4137352  PMID: 24524819
2.  Next-generation resorbable polymer scaffolds with surface-precipitated calcium phosphate coatings 
Regenerative Biomaterials  2015;2(1):1-8.
Next-generation synthetic bone graft therapies will most likely be composed of resorbable polymers in combination with bioactive components. In this article, we continue our exploration of E1001(1k), a tyrosine-derived polycarbonate, as an orthopedic implant material. Specifically, we use E1001(1k), which is degradable, nontoxic, and osteoconductive, to fabricate porous bone regeneration scaffolds that were enhanced by two different types of calcium phosphate (CP) coatings: in one case, pure dicalcium phosphate dihydrate was precipitated on the scaffold surface and throughout its porous structure (E1001(1k) + CP). In the other case, bone matrix minerals (BMM) such as zinc, manganese and fluoride were co-precipitated within the dicalcium phosphate dihydrate coating (E1001(1k) + BMM). These scaffold compositions were compared against each other and against ChronOS (Synthes USA, West Chester, PA, USA), a clinically used bone graft substitute (BGS), which served as the positive control in our experimental design. This BGS is composed of poly(lactide co-ε-caprolactone) and beta-tricalcium phosphate. We used the established rabbit calvaria critical-sized defect model to determine bone regeneration within the defect for each of the three scaffold compositions. New bone formation was determined after 2, 4, 6, 8 and 12 weeks by micro-computerized tomography (μCT) and histology. The experimental tyrosine-derived polycarbonate, enhanced with dicalcium phosphate dihydrate, E1001(1k) + CP, supported significant bone formation within the defects and was superior to the same scaffold containing a mix of BMM, E1001(1k) + BMM. The comparison with the commercially available BGS was complicated by the large variability in bone formation observed for the laboratory preparations of E1001(1k) scaffolds. At all time points, there was a trend for E1001(1k) + CP to be superior to the commercial BGS. However, only at the 6-week time point did this trend reach statistical significance. Detailed analysis of the μCT data suggested an increase in bone formation from 2 through 12 weeks in implant sites treated with E1001(1k) + CP. At 2 and 4 weeks post-implantation, bone formation occurred at the interface where the E1001(1k) + CP scaffold was in contact with the bone borders of the implant site. Thereafter, during weeks 6, 8 and 12 bone formation progressed throughout the E1001(1k) + CP test implants. This trend was not observed with E1001(1k) + BMM scaffolds or the clinically used BGS. Our results suggest that E1001(1k) + CP should be tested further for osteoregenerative applications.
PMCID: PMC4669025  PMID: 26813289
tyrosine-derived polycarbonate; dicalcium phosphate dihydrate; calcium phosphate; rabbit calvarial critical size defect model; bone regeneration
3.  TGF-β1 conjugated chitosan collagen hydrogels induce chondrogenic differentiation of human synovium-derived stem cells 
Unlike bone tissue, articular cartilage regeneration has not been very successful and has many challenges ahead. We have previously developed injectable hydrogels using photopolymerizable chitosan (MeGC) that supported growth of chondrocytes. In this study, we demonstrate a biofunctional hydrogel for specific use in cartilage regeneration by conjugating transforming growth factor-β1 (TGF-β1), a well-documented chondrogenic factor, to MeGC hydrogels impregnating type II collagen (Col II), one of the major cartilaginous extracellular matrix (ECM) components.
TGF-β1 was delivered from MeGC hydrogels in a controlled manner with reduced burst release by chemically conjugating the protein to MeGC. The hydrogel system did not compromise viability of encapsulated human synovium-derived mesenchymal stem cells (hSMSCs). Col II impregnation and TGF-β1 delivery significantly enhanced cellular aggregation and deposition of cartilaginous ECM by the encapsulated cells, compared with pure MeGC hydrogels.
This study demonstrates successful engineering of a biofunctional hydrogel with a specific microenvironment tailored to promote chondrogenesis. This hydrogel system can provide promising efficacious therapeutics in the treatment of cartilage defects.
Electronic supplementary material
The online version of this article (doi:10.1186/1754-1611-9-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4350967  PMID: 25745515
Chitosan hydrogels; Type II collagen; Transforming growth factor; Synovium-derived stem cells; Chondrogenic differentiation
4.  Osteoblast Growth and Bone Healing Response to Three Dimensional Poly(ε-caprolactone fumarate) Scaffolds 
Poly(ε-caprolactone fumarate) (PCLF) scaffold formulations were assessed as a delivery system of recombinant human bone morphogenetic protein (rhBMP-2) for bone tissue engineering. The formulations included PCLF with combinations of poly(vinyl alcohol) (PVA) and hydroxyapatite (HA). The assessments included in vitro and in vivo assays. In vitro assays validated cell attachment using a pre-osteoblast cell line (MC3T3-E1). Additionally, in vitro release profiles of rhBMP-2 from PCLF scaffolds were determined up to 21 days. Data suggested PCLF incorporated with PVA and HA accelerated rhBMP-2 release and the released protein was bioactive. For the in vivo study, a critical sized defect (CSD) model in a rabbit calvaria was used to test PCLF scaffolds. At 6 weeks post-implantation, significantly more bone formation was measured in PCLF scaffolds containing rhBMP-2 than in scaffolds without rhBMP-2. In conclusion, we demonstrated PCLF delivered biologically active rhBMP-2, promoted bone healing in a CSD and has potential as a bone tissue engineering scaffold.
PMCID: PMC3213277  PMID: 21744511
poly(ε-caprolactone fumarate); three-dimensional scaffold; rabbit calvarial critical sized defect; rhBMP-2; bone tissue engineering
5.  In Vivo Biodegradation and Biocompatibility of PEG/Sebacic Acid-Based Hydrogels using a Cage Implant System 
Comprehensive in vivo biodegradability and biocompatibility of unmodified and Arg-Gly-Asp (RGD) peptide-modified PEG/Sebacic acid based hydrogels were evaluated and compared to the control material poly(lactide-co-glycolide) (PLGA) using a cage implantation system, as well as direct subcutaneous implantation for up to 12 weeks. The total weight loss after 12 weeks of implantation for unmodified PEGSDA and RGD-modified PEGSDA in the cage was approximately 42% and 52%, respectively, with no statistical difference (p> 0.05). The exudate analysis showed that PEGSDA hydrogels induced minimal inflammatory response up to 21 days following implantation, similar to the controls (empty cage and the cage containing PLGA discs). Histology analysis from direct subcutaneous implantation of the hydrogels and PLGA scaffold showed statistically similar resolution of the acute and chronic inflammatory responses with development of the fibrous capsule between the PEGSDA hydrogels and the control (PLGA). The cage system, as well as the histology analysis, demonstrated that the degradation products of both hydrogels, with or without RGD peptide modification, are biocompatible without statistically significant differences in the inflammatory responses, as compared to PLGA.
PMCID: PMC2928850  PMID: 20574982
In vivo biocompatibility; In vivo biodegradation; PEG sebacic acid diacrylate; Hydrogel; RGD-modified hydrogel; Cage implantation
6.  Three-Dimensional Porous Biodegradable Polymeric Scaffolds Fabricated with Biodegradable Hydrogel Porogens 
We have developed a new fabrication technique to create three-dimensional (3D) porous poly(ε-caprolactone fumarate) (PCLF) scaffolds using hydrogel microparticle porogens, as an alternative to overcome certain limitations of traditional scaffold fabrication techniques such as a salt leaching method. Both natural hydrogel, gelatin, and synthetic hydrogel, poly(ethylene glycol) sebacic acid diacrylate, were used as porogens to fabricate 3D porous PCLF scaffolds. Hydrogel microparticles were prepared by a single emulsion technique with the particle size in the range of 100–500 μm after equilibrium in water. The pore size distribution, porosity, pore interconnectivity, and spatial pore heterogeneity of the 3D PCLF scaffolds were assessed using micro-computed tomography and imaging analysis. Scaffolds fabricated with the hydrogel porogens had higher porosity and pore interconnectivity as well as more homogeneous spatial pore distribution, compared to the scaffolds made from the salt leaching process. Compressive moduli of the scaffolds were also measured and showed that lower porosity yielded greater modulus of the scaffolds. Overall, the new fabrication technology using hydrogel porogens may be beneficial for certain tissue engineering applications.
PMCID: PMC2819712  PMID: 19216632
7.  Development of Biodegradable and Injectable Macromers Based on Poly(Ethylene Glycol) and Diacid Monomers 
Novel biodegradable injectable poly(ethylene glycol) (PEG) based macromers were synthesized by reacting low molecular weight PEG (MW: 200) and dicarboxylic acids such as sebacic acid or terephthalic acid. Chemical structures of the resulting polymers were confirmed by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy characterizations. Differential scanning calorimetry (DSC) showed that these polymers were completely amorphous above room temperature. After photopolymerization, dynamic elastic shear modulus of the crosslinked polymers was up to 1.5 MPa and compressive modulus was up to 2.2 MPa depending on the polymer composition. The in vitro degradation study showed that mass losses of these polymers were gradually decreased over 23 weeks of period in simulated body fluid. By incorporating up to 30 wt% of 2-hydroxyethyl methylmethacrylate (HEMA) into the crosslinking network, the dynamic elastic modulus and compressive modulus was significantly increased up to 7.2 MPa and 3.2 MPa, respectively. HEMA incorporation also accelerated degradation as indicated by significantly higher mass loss of up to 27% after 20 weeks of incubation. Cytocompatability studies using osteoblasts and neural cells revealed that cell metabolic activity on these polymers with or without HEMA was close to the control tissue culture polystyrene. The PEG based macromers developed in this study may be useful as scaffolds or cell carriers for tissue engineering applications.
PMCID: PMC2857720  PMID: 18655146
Polyethylene glycol; dicarboxylic acid; HEMA; tissue engineering; biodegradation
8.  Potential of Hydrogels Based on Poly(Ethylene Glycol) and Sebacic Acid as Orthopedic Tissue Engineering Scaffolds 
Tissue Engineering. Part A  2009;15(8):2299-2307.
In this study, the bioactive effects of poly(ethylene glycol) (PEG) sebacic acid diacrylate (PEGSDA) hydrogels with or without RGD peptide modification on osteogenic differentiation and mineralization of marrow stromal cells (MSCs) were examined. In a separate experiment, the ability of PEGSDA hydrogel to serve as a delivery vehicle for bone morphogenetic protein 2 (BMP-2) was also investigated. As a scaffold, the attachment and proliferation of MSCs on PEGSDA hydrogel scaffolds with and without RGD peptide modification was similar to the control, tissue culture polystyrene. In contrast, cells were barely seen on unmodified PEG diacrylate (PEGDA) hydrogel throughout the culture period for up to 21 days. Osteogenic phenotypic expression such as alkaline phosphatase (ALP) of MSCs as well as mineralized calcium content were significantly higher on PEGSDA-based hydrogels than those on the control or PEGDA hydrogels. Potential use of PEGSDA scaffold as a delivery vehicle of osteogenic molecules such as BMP-2 was also evaluated. Initial burst release of BMP-2 from PEGSDA hydrogel scaffold (14.7%) was significantly reduced compared to PEGDA hydrogel scaffold (84.2%) during the first 3 days of a 21-day release period. ALP activity of an osteoblast was significantly higher in the presence of BMP-2 released from PEGSDA hydrogel scaffolds compared to that in the presence of BMP-2 released from PEGDA scaffolds, especially after 6 days of release. Overall, PEGSDA hydrogel scaffolds without further modification may be useful as orthopedic tissue engineering scaffolds as well as local drug carriers for prolonged sustained release of osteoinductive molecules.
PMCID: PMC2792107  PMID: 19292677

Results 1-8 (8)