Polymer Scaffolds for Small-Diameter Vascular Tissue Engineering

To better engineer small-diameter blood vessels, a few types of novel scaffolds are fabricated from biodegradable poly( L -lactic acid) (PLLA) by means of thermally induced phase-separation (TIPS) techniques. By utilizing the differences in thermal conductivities of the mold materials and using benzene as the solvent scaffolds with oriented gradient microtubular structures in the axial or radial direction can be created. The porosity, tubular size, and the orientational direction of the microtubules can be controlled by the polymer concentration, the TIPS temperature, and by utilizing materials of different thermal conductivities. These gradient microtubular structures facilitate cell seeding and mass transfer for cell growth and function. Nanofibrous scaffolds with an oriented and interconnected microtubular pore network are also developed by a one-step TIPS method using a benzene/tetrahydrofuran mixture as the solvent without the need for porogen materials. The structural features of such scaffolds can be conveniently adjusted by varying the solvent ratio, phase-separation temperature, and polymer concentration to mimic the nanofibrous features of an extracellular matrix. These scaffolds were fabricated for the tissue engineering of small-diameter blood vessels by utilizing their advantageous structural features to facilitate blood-vessel regeneration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78073/1/2833_ftp.pd

From Nanofibrous Hollow Microspheres to Nanofibrous Hollow Discs and Nanofibrous Shells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115931/1/marc201500342.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115931/2/marc201500342-sup-0001-S1.pd

Macroporous and nanofibrous polymer scaffolds and polymer/bone-like apatite composite scaffolds generated by sugar spheres

Scaffolds are crucial to tissue engineering/regeneration. In this work, a technique combining a unique phase-separation process with a novel sugar sphere template leaching process has been developed to produce three-dimensional scaffolds. The resulting scaffolds possess high porosities, well connected macropores, and nanofibrous pore walls. The technique advantageously controls macropore shape and size by sugar spheres, interpore opening size by assembly conditions (time and temperature of heat treatment), and pore wall morphology by phase-separation parameters. The bioactivity of a macroporous and nanofibrous poly( L -lactic acid) (PLLA) scaffold was demonstrated by the bone-like apatite deposition throughout the scaffold in a simulated body fluid (SBF). Preincorporation of nanosized hydroxyapatite eliminated the induction period and facilitated the apatite growth in the SBF. Interestingly, the apatite growth primarily occurred on the surface of the pores (internal and external) but not the interior of the nanofibrous network away from the pore surface. It was also noticed that the macropore size did not affect the apatite growth rate, while the interpore opening size did. The compressive modulus also increased substantially when a continuous apatite layer was formed on the pore walls of the scaffold. The resulting composite scaffold mimics natural bone matrix with the combination of an organic phase (a polymer such as PLLA) and an inorganic apatite phase. The demonstrated bioactivity of apatite layer, together with well-controlled macroporous and nanofibrous structures, makes the novel nanocomposite scaffolds desirable for bone tissue engineering. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55803/1/30704_ftp.pd

Synthesis and Erosion Properties of PEG-Containing Polyanhydrides

To tailor the erosion rate of polyanhydrides while retaining their surface erosion characteristics, new three-component polyanhydrides of sebacic acid, 1,3-bis( p -carboxyphenoxy)propane and poly(ethylene glycol) were synthesized. The hydrophilicity of the polymer increased and its mechanical strength decreased with increasing PEG content. Correspondingly, the erosion rate increases with increasing PEG content, whereas it decreases with increasing specimen thickness. This indicates that the incorporation of poly(ethylene glycol) into traditional two-component polyanhydrides retains their surface erosion properties while making the erosion rate tunable. The new polyanhydrides hold potential for drug delivery applications.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56103/1/620_ftp.pd

Cell and biomolecule delivery for regenerative medicine

Regenerative medicine is an exciting field that aims to create regenerative alternatives to harvest tissues for transplantation. In this approach, the delivery of cells and biological molecules plays a central role. The scaffold (synthetic temporary extracellular matrix) delivers cells to the regenerative site and provides three-dimensional environments for the cells. To fulfil these functions, we design biodegradable polymer scaffolds with structural features on multiple size scales. To enhance positive cell–material interactions, we design nano-sized structural features in the scaffolds to mimic the natural extracellular matrix. We also integrate micro-sized pore networks to facilitate mass transport and neo tissue regeneration. We also design novel polymer devices and self-assembled nanospheres for biomolecule delivery to recapitulate key events in developmental and wound healing processes. Herein, we present recent work in biomedical polymer synthesis, novel processing techniques, surface engineering and biologic delivery. Examples of enhanced cellular/tissue function and regenerative outcomes of these approaches are discussed to demonstrate the excitement of the biomimetic scaffold design and biologic delivery in regenerative medicine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85429/1/stam10_1_014102.pd

Impact of pharmacologic inhibition of tooth movement on periodontal and tooth root tissues during orthodontic force application

ObjectiveThe goal of this study was to investigate potential negative sequelae of orthodontic force application ±delivery of an osteoclast inhibitor, recombinant osteoprotegerin protein (OPG‐Fc), on periodontal tissues.Setting and Sample PopulationSprague Dawley rats from a commercial supplier were investigated in a laboratory setting.Materials and MethodsRats were randomly divided into four groups (n = 7 each): one group with no orthodontic appliances and injected once prior to the experimental period with empty polymer microspheres, one group with orthodontic appliances and injected once with empty microspheres, one group with orthodontic appliances and injected once with polymer microspheres containing 1 mg/kg of OPG‐Fc, and one group with orthodontic appliances and injected with non‐encapsulated 5 mg/kg of OPG‐Fc every 3 days during the experimental period. The animals were euthanized after 28 days of tooth movement for histomorphometric analyses.ResultsRoot resorption, PDL area and widths were similar in animals without appliances and animals with appliances plus high‐dose OPG‐Fc. PDL blood vessels were compressed and decreased in number in all animals that received orthodontic appliances, regardless of OPG‐Fc. Hyalinization was significantly increased only in animals with orthodontic appliances plus multiple injections of 5 mg/kg non‐encapsulated OPG‐Fc when compared to animals without appliances.ConclusionsResults of this study indicate that while pharmacological modulation of tooth movement through osteoclast inhibition is feasible when delivered in a locally controlled low‐dose manner, high‐dose levels that completely prevent tooth movement through bone may decrease local blood flow and increase the incidence of hyalinization.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153668/1/ocr12350_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153668/2/ocr12350-sup-0001-FigS1-S2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153668/3/ocr12350.pd

Polymeric Scaffolds for Bone Tissue Engineering

Bone tissue engineering is a rapidly developing area. Engineering bone typically uses an artificial extracellular matrix (scaffold), osteoblasts or cells that can become osteoblasts, and regulating factors that promote cell attachment, differentiation, and mineralized bone formation. Among them, highly porous scaffolds play a critical role in cell seeding, proliferation, and new 3D-tissue formation. A variety of biodegradable polymer materials and scaffolding fabrication techniques for bone tissue engineering have been investigated over the past decade. This article reviews the polymer materials, scaffold design, and fabrication methods for bone tissue engineering. Advantages and limitations of these materials and methods are analyzed. Various architectural parameters of scaffolds important for bone tissue engineering (e.g. porosity, pore size, interconnectivity, and pore-wall microstructures) are discussed. Surface modification of scaffolds is also discussed based on the significant effect of surface chemistry on cells adhesion and function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44003/1/10439_2004_Article_482175.pd

Monodispersed Bioactive Glass Nanoclusters with Ultralarge Pores and Intrinsic Exceptionally High miRNA Loading for Efficiently Enhancing Bone Regeneration

Bioactive glass nanoparticles (BGNs) have attracted much attention in drug delivery and bone tissue regeneration, due to the advantages including biodegradation, high bone‐bonding bioactivity, and facile large‐scale fabrication. However, the wide biomedical applications of BGNs such as efficient gene delivery are limited due to their poor pore structure and easy aggregation. Herein, for the first time, this study reports novel monodispersed bioactive glass nanoclusters (BGNCs) with ultralarge mesopores (10–30 nm) and excellent miRNA delivery for accelerating critical‐sized bone regeneration. BGNCs with different size (100–500 nm) are fabricated by using a branched polyethylenimine as the structure director and catalyst. BGNCs show an excellent apatite‐forming ability and high biocompatibility. Importantly, BGNCs demonstrate an almost 19 times higher miRNA loading than those of conventional BGNs. Additionally, BGNCs–miRNA nanocomplexes exhibit a significantly high antienzymolysis, enhance cellular uptake and miRNA transfection efficiency, overpassing BGNs and commercial Lipofectamine 3000. BGNCs‐mediated miRNA delivery significantly improves the osteogenic differentiation of bone marrow stromal stem cells in vitro and efficiently enhances bone formation in vivo. BGNCs can be a highly efficient nonviral vector for various gene therapy applications. The study may provide a novel strategy to develop highly gene‐activated bioactive nanomaterials for simultaneous tissue regeneration and disease therapy.Monodispersed bioactive glass nanoclusters (BGNCs) with ultra‐large mesopores (10–30 nm) are developed for miRNA delivery to enhance bone regeneration. BGNCs demonstrated an ultrahigh miRNA loading and transfection efficiency, overpassing commercial lipofectamine. BGNCs‐mediated miRNA delivery significantly improved osteogenic differentiation of bone marrow stromal stem cells in vitro and enhanced bone formation in vivo.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139128/1/adhm201700630-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139128/2/adhm201700630.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139128/3/adhm201700630_am.pd

Synthetic θ‐Defensin Antibacterial Peptide as a Highly Efficient Nonviral Vector for Redox‐Responsive miRNA Delivery

Synthetic cationic vectors have shown great promise for nonviral gene delivery. However, their cytotoxicity and low efficiency impose great restrictions on clinic applications. To push through this limitation, humanized peptides or proteins with cationic biocompatibility as well as biodegradation would be an excellent candidate. Herein, for the first time, we describe how an arginine‐rich humanized antimicrobial cyclopeptide, θ‐defensin, can be used as a synthetic cationic vector to load and deliver miRNA into bone mesenchymal stem cells with high efficiency and ultralow cytotoxicity, surpassing the efficiency of the commercial polyethylenimine (25 kD) and Lipofectamine 3000. To note, θ‐defensin can redox‐responsively release the loaded miRNA through a structural change: in extracellular oxidative environment, θ‐defensin has large β‐sheet structures stabilized by three disulfide linkages, and this special structure enables highly efficient delivery of miRNA by passing through cell membranes; in intracellular environment, redox‐responsive disulfide linkages are broken and the tight β‐sheet structures are destroyed, so that the miRNA can be released. Our results suggest that synthetic θ‐defensin peptides are a new class of nonviral gene vectors and this study may also provide a promising strategy to design smart‐responsive gene vectors with high efficiency and minimal toxicity.This study describes how an arginine‐rich humanized antimicrobial cyclopeptide, θ‐defensin, can be used as a synthetic cationic vector to load and deliver miRNA into bone mesenchymal stem cells with high efficiency and low cytotoxicity, surpassing the efficiency of the commercial polyethylenimine (25 kD) and Lipofectamine 3000.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141894/1/adbi201700001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141894/2/adbi201700001_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141894/3/adbi201700001-sup-0001-S1.pd

Microspheres Assembled from Chitosan‐Graft‐Poly(lactic acid) Micelle‐Like Core–Shell Nanospheres for Distinctly Controlled Release of Hydrophobic and Hydrophilic Biomolecules

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/122426/1/mabi201600020-sup-0001-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/122426/2/mabi201600020.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/122426/3/mabi201600020_am.pd