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Choi S.,University of Wisconsin - Madison | Murphy W.L.,University of Wisconsin - Madison | Murphy W.L.,Foundation Collaborative Research Center
Journal of Materials Chemistry | Year: 2012

Previous studies have demonstrated the influence of calcium phosphate (CaP) mineral coating characteristics on cell attachment, proliferation, and differentiation. However, the wide range of mineral properties that can potentially influence cell behavior calls for an efficient platform to screen for the effects of specific mineral properties. To address this need, we have developed an efficient well-plate format to probe for the effects of mineral coating properties on stem cell behavior. Specifically, here we systematically controlled mineral coating morphology by modulating ion concentrations in modified simulated body fluids (mSBF) during mineral nucleation and growth. We found that mineral micro-morphology could be gradually changed from spherulitic, to plate-like, to net-like depending on [Ca2+] and [PO 4 3-] in mSBF solutions, while other mineral properties (Ca/P ratio, crystallinity, dissolution rate) remained constant. Differences in mineral morphology resulted in significant differences in stem cell attachment and expansion in vitro. These findings suggest that an enhanced throughput mineral coating format may be useful to identify mineral coating properties for optimal stem cell attachment and expansion, which may ultimately permit efficient intraoperative seeding of patient derived stem cells. © 2012 The Royal Society of Chemistry.

Choi S.,University of Wisconsin - Madison | Murphy W.L.,University of Wisconsin - Madison | Murphy W.L.,Foundation Collaborative Research Center
Biotechnology Journal | Year: 2013

"Biomimetic" inorganic coating on biomaterials has been an active area of research with the aim of providing bioactive surfaces that can regulate cell behavior. Previous studies have demonstrated that human mesenchymal stem cell (hMSC) behavior is differentially regulated by the physical and chemical properties of inorganic mineral coatings, indicating that modulation of mineral properties is potentially important in regulating hMSC behavior. However, the lack of an efficient experimental context, in which to study stem cell behavior on inorganic substrates, has made it difficult to systematically study the effects of specific mineral coating parameters on hMSC behavior. In this study, we developed an efficient experimental platform to screen for the effects of mineral coating morphology on hMSC expansion and differentiation. hMSC expansion on mineral coatings was regulated by the micro-scale morphology of these coatings, with greater expansion on small granule-like coatings when compared to plate-like or net-like coatings. In contrast, hMSC osteogenic differentiation was inversely correlated with cell expansion on mineral coatings indicating that mineral coating morphology was a key parameter that regulates hMSC differentiation. The effect of mineral coating morphology on hMSC behavior underlines the utility of this inorganic screening platform to identify optimal coatings for medical devices and bone tissue engineering applications. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Suarez-Gonzalez D.,University of Wisconsin - Madison | Lee J.S.,University of Wisconsin - Madison | Diggs A.,University of Michigan | Lu Y.,University of Wisconsin - Madison | And 5 more authors.
Tissue Engineering - Part A | Year: 2014

It is known that angiogenesis plays an important role in bone regeneration and that release of angiogenic and osteogenic growth factors can enhance bone formation. Multiple growth factors play key roles in processes that lead to tissue formation/regeneration during natural tissue development and repair. Therefore, treatments aiming to mimic tissue regeneration can benefit from multiple growth factor release, and there remains a need for simple clinically relevant approaches for dual growth factor release. We hypothesized that mineral coatings could be used as a platform for controlled incorporation and release of multiple growth factors. Specifically, mineral-coated scaffolds were "dip coated" in multiple growth factor solutions, and growth factor binding and release were dictated by the growth factor-mineral binding affinity. Beta tricalcium phosphate (β-TCP) scaffolds were fabricated using indirect solid-free form fabrication techniques and coated with a thin conformal mineral layer. Mineral-coated β-TCP scaffolds were sequentially dipped in recombinant human vascular endothelial growth factor (rhVEGF) and a modular bone morphogenetic peptide, a mineral-binding version of bone morphogenetic protein 2 (BMP2), solutions to allow for the incorporation of each growth factor. The dual release profile showed sustained release of both growth factors for over more than 60 days. Scaffolds releasing either rhVEGF alone or the combination of growth factors showed an increase in blood vessel ingrowth in a dose-dependent manner in a sheep intramuscular implantation model. This approach demonstrates a "modular design" approach, in which a controllable biologics carrier is integrated into a structural scaffold as a thin surface coating. © Mary Ann Liebert, Inc.

Solorio L.D.,Case Western Reserve University | Phillips L.M.,Case Western Reserve University | Mcmillan A.,Case Western Reserve University | Cheng C.W.,Case Western Reserve University | And 7 more authors.
Advanced Healthcare Materials | Year: 2015

Giving rise to both bone and cartilage during development, bone marrow-derived mesenchymal stem cells (hMSC) have the unique capacity to generate the complex tissues of the osteochondral interface. Utilizing a scaffold-free hMSC system, biphasic osteochondral constructs are incorporated with two types of growth factor-releasing microparticles to enable spatially organized differentiation. Gelatin microspheres (GM) releasing transforming growth factor-β1 (TGF-β1) combined with hMSC form the chondrogenic phase. The osteogenic phase contains hMSC only, mineral-coated hydroxyapatite microparticles (MCM), or MCM loaded with bone morphogenetic protein-2 (BMP-2), cultured in medium with or without BMP-2. After 4 weeks, TGF-β1 release from GM within the cartilage phase promotes formation of a glycosaminoglycan- and type II collagen-rich matrix, and has a local inhibitory effect on osteogenesis. In the osteogenic phase, type X collagen and osteopontin are produced in all conditions. However, calcification occurs on the outer edges of the chondrogenic phase in some constructs cultured in media containing BMP-2, and alkaline phosphatase levels are elevated, indicating that BMP-2 releasing MCM provides better control over region-specific differentiation. The production of complex, stem cell-derived osteochondral tissues via incorporated microparticles could enable earlier implantation, potentially improving outcomes in the treatment of osteochondral defects. A stem cell-derived, biphasic osteochondral construct is engineered with transforming growth factor-β1-releasing hydrogel microspheres in the chondrogenic phase and bone morphogenetic protein-2-releasing hydroxyapatite microparticles in the osteogenic phase. Results demonstrate, for the first time, that spatial control of osteochondral differentiation can be achieved in a scaffold-free cellular construct via the incorporation of bioactive microparticles. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Yu X.,University of Wisconsin - Madison | Khalil A.,University of Wisconsin - Madison | Dang P.N.,Case Western Reserve University | Alsberg E.,Case Western Reserve University | And 3 more authors.
Advanced Functional Materials | Year: 2014

There is an increasing need to control the type, quantity, and timing of growth factors released during tissue healing. Sophisticated delivery systems offering the ability to deliver multiple growth factors with independently tunable kinetics are highly desirable. Here, a multilayered, mineral coated microparticle (MCMs) platform that can serve as an adaptable dual growth factor delivery system is developed. Bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) are bound to the mineral coatings with high binding efficiencies of up to 80%. BMP-2 is firstly bound onto a 1st mineral coating layer; then VEGF is bound onto a 2nd mineral coating layer. The release of BMP-2 is sustained over a period of 50 days while the release of VEGF is a typical two-phase release with rapid release in the first 14 days and more sustained release for the following 36 days. Notably, the release behaviors of both growth factors can be independently tailored by changing the intrinsic properties of the mineral coatings. Furthermore, the release of BMP-2 can be tuned by changing the thickness of the 2nd layer. This injectable microparticle based delivery platform with tunable growth factor release has immense potential for applications in tissue engineering and regenerative medicine. A multilayered, mineral coated microparticle platform is developed for tunable dual growth factor delivery. Distinct release kinetics of BMP-2 and VEGF is achieved by binding the growth factors on different coating layers and manipulating the intrinsic properties of the mineral coatings. This multiple protein delivery system has immense potential in tissue engineering to better mimic the natural healing process. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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