Peter X. Ma

Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: part 1. Structure, gelation rate and mechanical properties.

Alginate gels have been used in both drug delivery and cell encapsulation applications in the bead form usually produced by dripping alginate solution into a CaCl2 bath. The major disadvantages to these systems are that the gelation rate is hard to control; the resulting structure is not uniform; and mechanically strong and complex-shaped 3-D structures are difficult to achieve. In this work controlled gelation rate was achieved with CaCO3-GDL and CaSO4-CaCO3-GDL systems, and homogeneous alginate gels were formulated as scaffolds with defined dimensions for tissue engineering applications. Gelation rate increased with increasing total calcium content, increasing proportion of CaSO4, increasing temperature and decreasing alginate concentration. Mechanical properties of the alginate gels were controlled by the compositional variables. Slower gelation systems generate more uniform and mechanically stronger gels than faster gelation systems. The compressive modulus and strength increased with alginate concentration, total calcium content, molecular weight and guluronic acid (G) content of the alginate. MC3T3-E1 osteoblastic cells were uniformly incorporated in the alginate gels and cultured in vitro. These results demonstrated how alginate gel and gel/cell systems could be formulated with controlled structure, gelation rate, and mechanical properties for tissue engineering and other biomedical applications.

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.

Synthetic nano-scale fibrous extracellular matrix

Biodegradable polymers have been widely used as scaffolding materials to regenerate new tissues. To mimic natural extracellular matrix architecture, a novel highly porous structure, which is a three-dimensional interconnected fibrous network with a fiber diameter ranging from 50 to 500 nm, has been created from biodegradable aliphatic polyesters in this work. A porosity as high as 98.5% has been achieved. These nano-fibrous matrices were prepared from the polymer solutions by a procedure involving thermally induced gelation, solvent exchange, and freeze-drying. The effects of polymer concentration, thermal annealing, solvent exchange, and freezing temperature before freeze-drying on the nano-scale structures were studied. In general, at a high gelation temperature, a platelet-like structure was formed. At a low gelation temperature, the nano-fibrous structure was formed. Under the conditions for nano-fibrous matrix formation, the average fiber diameter (160-170 nm) did not change statistically with polymer concentration or gelation temperature. The porosity decreased with polymer concentration. The mechanical properties (Youngs modulus and tensile strength) increased with polymer concentration. A surface-to-volume ratio of the nano-fibrous matrices was two to three orders of magnitude higher than those of fibrous nonwoven fabrics fabricated with the textile technology or foams fabricated with a particulate-leaching technique. This synthetic analogue of natural extracellular matrix combined the advantages of synthetic biodegradable polymers and the nano-scale architecture of extracellular matrix, and may provide a better environment for cell attachment and function.

Poly(α-hydroxyl acids)/hydroxyapatite porous composites for bone-tissue engineering. I. Preparation and morphology

Tissue engineering has shown great promise for creating biological alternatives for implants. In this approach, scaffolding plays a pivotal role. Hydroxyapatite mimics the natural bone mineral and has shown good bone-bonding properties. This paper describes the preparation and morphologies of three-dimensional porous composites from poly(L-lactic acid) (PLLA) or poly(D,L-lactic acid-co-glycolic acid) (PLGA) solution and hydroxyapatite (HAP). A thermally induced phase separation technique was used to create the highly porous composite scaffolds for bone-tissue engineering. Freeze drying of the phase-separated polymer/HAP/solvent mixtures produced hard and tough foams with a co-continuous structure of interconnected pores and a polymer/HAP composite skeleton. The microstructure of the pores and the walls was controlled by varying the polymer concentration, HAP content, quenching temperature, polymer, and solvent utilized. The porosity increased with decreasing polymer concentration and HAP content. Foams with porosity as high as 95% were achieved. Pore sizes ranging from several microns to a few hundred microns were obtained. The composite foams showed a significant improvement in mechanical properties over pure polymer foams. They are promising scaffolds for bone-tissue engineering.

Scaffolds for tissue fabrication

Abstract Tissue engineering is an interdisciplinary and multidisciplinary field. It has shown great promise in generating living alternatives for harvested tissues and organs for transplantation and reconstructive surgery. Materials and fabrication technologies are critically important for tissue engineering in designing temporary, artificial extracellular matrices (scaffolds), which support three-dimensional tissue formation. This review briefly introduces the concept of tissue engineering, and illustrates the relationship between tissue engineering and materials science and engineering. Important scaffold design principles are described. The most frequently used materials and fabrication technologies for scaffolds are reviewed. Some exciting new developments in scaffold materials and fabrication technologies are also discussed.

Biodegradable Polymer Scaffolds with Well-Defined Interconnected Spherical Pore Network

Scaffolding plays pivotal role in tissue engineering. In this work, a novel processing technique has been developed to create three-dimensional biodegradable polymer scaffolds with well-controlled interconnected spherical pores. Paraffin spheres were fabricated with a dispersion method, and were bonded together through a heat treatment to form a three-dimensional assembly in a mold. Biodegradable polymers such as PLLA and PLGA were dissolved in a solvent and cast onto the paraffin sphere assembly. After dissolving the paraffin, a porous polymer scaffold was formed. The fabrication parameters were studied in relation to the pore shape, interpore connectivity, pore wall morphology, and mechanical properties of the polymer scaffolds. The compressive modulus of the scaffolds decreased with increasing porosity. Longer heat treatment time of the paraffin spheres resulted in larger openings between the pores of the scaffolds. Foams of smaller pore size (100-200 microm) resulted in significantly lower compressive modulus than that of larger pore sizes (250-350 or 420-500 microm). The PLLA foams had a skeletal structure consisting of small platelets, whereas PLGA foams had homogeneous skeletal structure. The new processing technique can tailor the polymer scaffolds for a variety of potential tissue engineering applications because of the well-controlled architecture, interpore connectivity, and mechanical properties.

Engineering new bone tissue in vitro on highly porous poly(α-hydroxyl acids)/hydroxyapatite composite scaffolds

Engineering new bone tissue with cells and a synthetic extracellular matrix (scaffolding) represents a new approach for the regeneration of mineralized tissues compared with the transplantation of bone (autografts or allografts). In the present work, highly porous poly(L-lactic acid) (PLLA) and PLLA/hydroxyapatite (HAP) composite scaffolds were prepared with a thermally induced phase separation technique. The scaffolds were seeded with osteoblastic cells and cultured in vitro. In the pure PLLA scaffolds, the osteoblasts attached primarily on the outer surface of the polymer. In contrast, the osteoblasts penetrated deep into the PLLA/HAP scaffolds and were uniformly distributed. The osteoblast survival percentage in the PLLA/HAP scaffolds was superior to that in the PLLA scaffolds. The osteoblasts proliferated in both types of the scaffolds, but the cell number was always higher in the PLLA/HAP composite scaffolds during 6 weeks of in vitro cultivation. Bone-specific markers (mRNAs encoding bone sialoprotein and osteocalcin) were expressed more abundantly in the PLLA/HAP composite scaffolds than in the PLLA scaffolds. The new tissue increased continuously in the PLLA/HAP composite scaffolds, whereas new tissue formed only near the surface of pure PLLA scaffolds. These results demonstrate that HAP imparts osteoconductivity and the highly porous PLLA/HAP composite scaffolds are superior to pure PLLA scaffolds for bone tissue engineering.

Biomimetic nanofibrous scaffolds for bone tissue engineering

Bone tissue engineering is a highly interdisciplinary field that seeks to tackle the most challenging bone-related clinical issues. The major components of bone tissue engineering are the scaffold, cells, and growth factors. This review will focus on the scaffold and recent advancements in developing scaffolds that can mimic the natural extracellular matrix of bone. Specifically, these novel scaffolds mirror the nanofibrous collagen network that comprises the majority of the non-mineral portion of bone matrix. Using two main fabrication techniques, electrospinning and thermally-induced phase separation, and incorporating bone-like minerals, such as hydroxyapatite, composite nanofibrous scaffolds can improve cell adhesion, stem cell differentiation, and tissue formation. This review will cover the two main processing techniques and how they are being applied to fabricate scaffolds for bone tissue engineering. It will then cover how these scaffolds can enhance the osteogenic capabilities of a variety of cell types and survey the ability of the constructs to support the growth of clinically relevant bone tissue.

Biomimetic nanofibrous gelatin/apatite composite scaffolds for bone tissue engineering

Mimicking certain features (e.g. nanoscale topography and biological cues) of natural extracellular matrix (ECM) is advantageous for the successful regeneration of damaged tissue. In this study, nanofibrous gelatin/apatite (NF-gelatin/apatite) composite scaffolds have been fabricated to mimic both the physical architecture and chemical composition of natural bone ECM. A thermally induced phase separation (TIPS) technique was developed to prepare nanofibrous gelatin (NF-gelatin) matrix. The NF-gelatin matrix mimicked natural collagen fibers and had an average fiber diameter of about 150nm. By integrating the TIPS method with porogen leaching, three-dimensional NF-gelatin scaffolds with well-defined macropores were fabricated. In comparison to Gelfoam (a commercial gelatin foam) with similar pore size and porosity, the NF-gelatin scaffolds exhibited a much higher surface area and mechanical strength. The surface area and compressive modulus of NF-gelatin scaffolds were more than 700 times and 10 times higher than that of Gelfoam, respectively. The NF-gelatin scaffolds also showed excellent biocompatibility and mechanical stability. To further enhance pre-osteoblast cell differentiation as well as improving mechanical strength, bone-like apatite particles (<2microm) were incorporated onto the surface of NF-gelatin scaffolds via a simulated body fluid (SBF) incubation process. The NF-gelatin/apatite scaffolds 5 days after SBF treatment showed significantly higher mechanical strength than NF-gelatin scaffolds 5 days after SBF treatment. Furthermore, the incorporated apatite in the NF-gelatin/apatite composite scaffold enhanced the osteogenic differentiation. The expression of BSP and OCN in the osteoblast-(NF-gelatin/apatite composite) constructs was about 5 times and 2 times higher than in the osteoblast-(NF-gelatin) constructs 4 weeks after cell culture. The biomimetic NF-gelatin/apatite scaffolds are, therefore, excellent for bone tissue engineering.

Cyclodextrin-based supramolecular systems for drug delivery: Recent progress and future perspective

The excellent biocompatibility and unique inclusion capability as well as powerful functionalization capacity of cyclodextrins and their derivatives make them especially attractive for engineering novel functional materials for biomedical applications. There has been increasing interest recently to fabricate supramolecular systems for drug and gene delivery based on cyclodextrin materials. This review focuses on state of the art and recent advances in the construction of cyclodextrin-based assemblies and their applications for controlled drug delivery. First, we introduce cyclodextrin materials utilized for self-assembly. The fabrication technologies of supramolecular systems including nanoplatforms and hydrogels as well as their applications in nanomedicine and pharmaceutical sciences are then highlighted. At the end, the future directions of this field are discussed.