Polymer Nanocomposites for Medical Applications

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1 Department of Bioengineering Liu Research Group www. Liugroup.org Polymer Nanocomposites for Medical Applications Huinan Liu, Ph.D. Department of Bioengineering Interdisciplinary Materials Science and Engineering Program Bourns College of Engineering The Stem Cell Center Inland Empire Stem Cell Consortium University of California at Riverside Contact: Faculty Website: Research Overview and Multidisciplinary Collaborations Liu Research Group www. Liugroup.org Nanocomposites Ceramic Nanoparticles Biodegradable Metals Biodegradable Polymers/Hydrogels Biodegradable Materials & Nanostructured Interfaces Nanostructured Surfaces/Coatings Material Design, Synthesis & Characterization Implant/Device Fabrication & Evaluation Cellular Responses In vitro Assessment Nerve Controlled Drug Delivery Regenerative Medicine Bone Cartilage Ligament Infection In vivo Evaluation: Functionality in Animal Models Pre Clinical Models & Clinical Trials Medical Device & Implant Industry Design Objectives FDA Clinicians/Surgeons 1

2 Interface between Biomaterials and Cells Fascinating! Diversity and Complexity of Life at the Cellular Level Liu H. Nanocomposites for Orthopedic Tissue Regeneration and Drug Delivery: Promise and Challenge. VDM Verlag. ISBN Can we control them? Cipriano AF, Sallee A, Guan R, Zhao Z, Tayoba M, Sanchez J, and Liu H. Investigation of Magnesium Zinc Calcium Alloys and Bone Marrow Derived Mesenchymal Stem Cell Response in Direct Culture. Acta Biomaterialia. 12: , 215. How Biomaterials Affect Cell Behaviors? Performance Composition Micro/Nano Structure Properties Synthesis/Processing Cell Behaviors Material Chemistry Mechanical Properties Surface Properties 2

3 Biomaterials and Cell Behaviors: Multiple Factors and Complexity Purity Composition Degradation products Material Chemistry Cell Behaviors Modulus/stiffness Strength Flexibility Fracture toughness Mechanical Properties Surface Properties Surface area Surface roughness Surface energy Hydrophilicity/hydrophobicity Surface features: size and shape Surface patterns: size, shape and orientation Environmental Factors In vitro variables: media, proteins, cells In vivo variables: anatomical locations, diversity (need for personalized medicine) Scale is Important at the Interface of Biomaterials and Cells A biomaterial is a (nonviable) material used in a medical device, intended to interact with biological systems Interactions between Biomaterials and Cells: Scale is Important Even if Other Factors are Constant Biomaterial Nano scale Micron scale Macro scale Biological Systems Protein level Cell level Tissue level Williams, D.F. (1987) Definitions in Biomaterials. Proceedings of a Consensus Conference of the European Society For Biomaterials, England, 1986, Elsevier, New York. 3

4 Osteoblast Functions: Scale is Important for Cells Calcium Concentration (microgram calcium/mg protein) microns Conventional Titania Alumina Titania Hydroxyapatite Glass Grain Size (nm) Culture medium = DMEM supplemented with 1% fetal bovine serum, 5 μg/ml L ascorbate and 1 mm b glycerophosphate. Culture time = 28 days. Values are mean ± SEM; n = 3; p <.1 (compared to respective conventional grain size ceramic). Webster TJ, Siegel RW, Bizios R. Enhanced functions of osteoblasts on nanophase ceramics. Biomaterials. 21: , microns Nanophase Titania Cell Adhesion on Surface: Scale is Important Liu H and Webster TJ. Nanomedicine for Implants: A Review of Studies and Necessary Experimental Tools. Biomaterials. 28(2): , 27. (PMID: ) 4

5 Fibronectin Interactions with Nano-scale Surfaces: Scale is Important for Proteins a b AFM images of fibronectin (5 µg/ml) adsorbed to PLGA surface with (a,b) 5 nm, (c,d) 2 nm and (e,f) 1 nm spherical features. Scan size=75 nm X 75 nm Scale bars=15 nm. Little to no interconnectivity A higher degree of interconnectivity c d Well spread with a large amount of interconnectivity e f Miller DC, Haberstroh KM, Webster TJ.PLGA nanometer surface features manipulate fibronectin interactions for improved vascular cell adhesion. J Biomed Mater Res A. 27 Jun 1;81(3): How can we use this idea to improve biomaterials for tissue regeneration? 5

6 Nanocomposites for Bone Regeneration Surface Properties and Cell Functions Cell Interactions with 3D Structures Drug Delivery Controlled Degradation Mechanical Properties Ceramic/Polymer Nanocomposites Nanofabrication: 2D and 3D structures Osteoblast Adhesion on Nanocomposites PTCa PLGA PTCa: Agglomerated PTCd: Dispersed Magnification bars: 1 µm PTCd TCS 18H t L 2 D ( p L) g Liu H, Slamovich EB and Webster TJ. Increased Osteoblast Functions among Nanophase Titania/Poly(lactide-co-glycolide) Composites of the Highest Nanometer Surface Roughness. Journal of Biomedical Materials Research. 78A(4): , 26. Surface Roughness Osteoblast Adhesion nm PLGA PTCa PTCd TCS Bone Cells/cm 2 PLGA PTCa PTCd TCS 6

7 Nanocomposites: 3D Printed Structures Liu H and Webster TJ. Enhanced Biological and Mechanical Properties of Well- Dispersed Nanophase Ceramics in Polymer Composites: From 2D to 3D Printed Structures. Materials Science and Engineering: C. 31(2): 77-89, 211. SEM micrograph of 3D nanocomposite structure 3D printed nanocomposite using Optomec s Aerosol Jet SEM micrograph of a magnified region of the 3D printed nanocomposite surface Bar=1 µm Bar=2 nm Promoted Osteoblast Infiltration into 3D Nanocomposites Cells SEM micrograph of an osteoblast adhering on the nanocomposite surface. Bar=1 µm. Confocal micrograph of osteoblasts adhering into porous structures of 3D nanocomposite scaffold. Bar=15 µm. Liu H and Webster TJ. Enhanced Biological and Mechanical Properties of Well-Dispersed Nanophase Ceramics in Polymer Composites: From 2D to 3D Printed Structures. Materials Science and Engineering: C. 31(2): 77-89,

8 Human Mesenchymal Stem Cells (hmsc) Adhesion and Osteogenic Differentiation Nanophase HA_PLGA: 3D Interconnected Glass Control: 2D flat hmsc Adhesion Density (cells/cm 2 ) Calcium Deposition (µg/cm 2 ) # # HA_Ps_PLGA 2 HA_PLGA 3 HA_Ps 4 HA 5 PLGA_P 6 PLGA 7 DIF 7c Peptide 8 Glass 9 PSTC Lock JY, Liu H. Nanomaterials Enhanced Osteogenic Differentiation of Human Mesenchymal Stem Cells Similar to a Short Peptide of BMP-7. International Journal of Nanomedicine. 6: , 211. hmscs: ALP Activity and Calcium Deposition Lock JY, Nguyen TY, and Liu H. Nanophase Hydroxyapatite and Poly(lactide-co-glycolide) Composites Promote Human Mesenchymal Stem Cell Adhesion and Osteogenic Differentiation In Vitro. Journal of Materials Science: Materials in Medicine. 23(1): ,

9 Mechanical Properties of Polymer Nanocomposites a: agglomerated d: dispersed Tensile Modulus (MPa) Tensile Strength (MPa). PLGA PTCa PTCd PLGA PTCa PTCd Values are mean ± SEM; n = 3; p <.5comparedtoPLGA;p <.5comparedtoPTCa Tensile Strength at Yield UTS Liu H and Webster TJ. Mechanical Properties of Dispersed Ceramic Nanoparticles in Polymer Composites for Orthopedic Applications. International Journal of Nanomedicine. 5: , 21. (PMID: ) Next-Generation Load-Bearing Implants Biodegradable and Bioresorbable Fracture Implantation Healing Restored Bone Conventional: Permanent metallic implant (e.g., titanium) Revision surgery needed to remove implant Bioresorbable Metallic Fixation Devices Control Cellular Functions, Implant Degradation and Tissue Interactions Tissue Regenerated and Implant Disappeared 9

10 HA Nanoparticles: the Coating Material for Bone Interface Nanophase Hydroxyapatite under SEM HA: Ca 1 (PO 4 ) 6 (OH) 2 Size range: 19 to 58 nm Average particle size: 34 nm Tian Q, and Liu H. Electrophoretic Deposition and Characterization of Nanocomposites and Nanoparticles on Magnesium Substrates. Nanotechnology. 26(17): 17512, April 215. (PMID: ) Translational Research From Bench top to Bedside Multifunctional Nanocoatings for Implants NanoSpray System for Medical Coatings MultiCare Nanocoating Dental Implant Hip Implants Liu H, Jiang W and Malshe A. Novel Nanostructured Hydroxyapatite Coating for Dental and Orthopedic Implants. JOM. 61(9): 67-69, 29. 1

11 Nanophase Hydroxyapatite Coating on Mg Alloys KCnt 1.5 O Mg P Ca/P Ratio =1.6 Ca Close to HA Ca/P Ratio =1.66 C Ca Energy kev SEM image (25x) nha coated Mg EDS analysis of nha coated Mg Iskandar ME, Aslani A, and Liu H. The Effects of Nanostructured Hydroxyapatite Coating on the Biodegradation and Cytocompatibility of Magnesium Implants. Journal of Biomedical Materials Research Part A. 11(8): , 213. Nanocomposite Coating on Biodegradable Magnesium Alloys 5 nm Serve as Dual Functions: Promote Bone Cell Adhesion and Reduce Substrate Degradation Rate Tian Q, and Liu H. Electrophoretic Deposition and Characterization of Nanocomposites and Nanoparticles on Magnesium Substrates. Nanotechnology. 26(17): 17512, April 215. (PMID: ) 11

12 Magnetic Nanocomposites 2 μm A B t= s t=1 s t=1.5 s t=2 s t= s t=3 s Magnetic responses of the synthesized MagGel and magnetic nanoparticles to a magnet. (A) MagGel in MES buffer (unit of numbers in red: mm) and (B) magnetic nanoparticles in DI water. Blue arrows indicate the object movement direction before next time point. Zhang N, Lock J, Sallee A, and Liu H. Magnetic Nanocomposite Hydrogel for Potential Cartilage Tissue Engineering: Synthesis, Characterization, and Cytocompatibility with Bone Marrow Derived Mesenchymal Stem Cells. ACS Applied Materials and Interfaces. Accepted 8/28/215. DOI: 1.121/acsami.5b6939. Magnetic Guidance am5b6939_si_1.avi Zhang N, Lock J, Sallee A, and Liu H. Magnetic Nanocomposite Hydrogel for Potential Cartilage Tissue Engineering: Synthesis, Characterization, and Cytocompatibility with Bone Marrow Derived Mesenchymal Stem Cells. ACS Applied Materials and Interfaces. Accepted 8/28/215. DOI: 1.121/acsami.5b

13 Synthesis of Magnetic Nanocomposites B PVA Magnetic Nanoparticles n 5 nm Hybrid Gel 4-arm PEG Hyaluronic Acid (HA) Zhang N, Lock J, Sallee A, and Liu H. Magnetic Nanocomposite Hydrogel for Potential Cartilage Tissue Engineering: Synthesis, Characterization, and Cytocompatibility with Bone Marrow Derived Mesenchymal Stem Cells. ACS Applied Materials and Interfaces. Accepted 8/28/215. DOI: 1.121/acsami.5b6939. Type II Collagen Degradation of Magnetic Nanocomposites A Day B Day Zhang N, Lock J, Sallee A, and Liu H. Magnetic Nanocomposite Hydrogel for Potential Cartilage Tissue Engineering: Synthesis, Characterization, and Cytocompatibility with Bone Marrow Derived Mesenchymal Stem Cells. ACS Applied Materials and Interfaces. Accepted 8/28/215. DOI: 1.121/acsami.5b

14 Cytocompatibility of Magnetic Nanocomposites 5 μm MagGel Control Hybrid Gel Magnetic Nanoparticles Summary Polymer nanocomposites are engineered to control biological interactions at the cellular level at the protein level at the tissue level, hopefully in the future studies Polymer nanocomposites with well-dispersed HA nanoparticles promote osteogenic differentiation of BMSCs provide dual functions on biodegradable Mg substrates - modulate bone integration and implant degradation Magnetic nanocomposites are engineered for remote magnetic guidance biodegradable cytocompatible with BMSCs future studies on in vivo assessment 14