An approach to integrating shape and biomedical attributes in vascular models

Computational models have been used widely in tissue engineering research and have proven to be powerful tools for bio-mechanical analysis (i.e., blood flow, growth models, drug delivery, etc). This paper focuses on developing higher-fidelity models for vascular structures and blood vessels that integrate computational shape representations with biomedical properties and features. Previous work in computer-aided vascular modeling comes from two communities. For those in biomedical imaging, the goal of past research has been to develop image understanding techniques for the interpretation of x-ray, magnetic resonance imaging (MRI), or other radiological data. These representations are predominantly discrete shape models that are not tied to physiological properties. The other corpus of existing work comes from those interested in developing physiological models for vascular growth and behavior based on bio-medical attributes. These models usually either have a highly simplified shape representation, or lack one entirely. Further, neither of these representations are suitable for the kind of interactive modeling required by tissue engineering applications.This paper aims to bridge these two approaches and develop a set of mathematical tools and algorithms for feature-based representation and computer-aided modeling of vascular trees for use in computer-aided tissue engineering applications. The paper offers a multi-scale representation based on swept volumes and a feature-based representation that can attribute the geometric representation with information about blood flow, pressure, and other biomedical properties. The paper shows how the resulting representation can be used as part of an overall approach for designing and visualizing vascular scaffolds. As a real-world example, we show how this computational model can be used to develop a tissue scaffold for liver tissue engineering. Such scaffolds may prove useful in a number of biomedical applications, including the growth of replacement tissue grafts and in vitro study of the pharmacological affects of new drugs on tissue cultures.     

Topology optimization of three dimensional tissue engineering scaffold architectures for prescribed bulk modulus and diffusivity

Tissue engineering scaffolds play critical roles in skeletal tissue regeneration by supporting physiological loads as well as enhancing cell/tissue migration and formation. These roles can be fulfilled by the functional design of scaffold pore architectures such that the scaffold provides proper mechanical and mass transport environments for new tissue formation. These roles require simultaneous design of mechanical and mass transport properties. In this paper, a numerical homogenization based topology optimization scheme was applied to the design of three dimensional unit microstructures for tissue engineering scaffolds. As measures of mechanical and mass transport environments, target effective bulk modulus and isotropic diffusivity were achieved by optimal design of porous microstructure. Cross property bounds between bulk modulus and diffusivity were adapted to determine feasible design targets for a given porosity. Results demonstrate that designed microstructures could reach cross property bounds for porosity ranging from 30% to 60%.     

用软刻蚀制备组织工程3D聚合物微结构

软刻蚀制备组织工程3D可生物降解、生物相容性好的几何图案聚合物微结构,方法简单,使用聚二甲基硅氧烷(PDMS)作为弹性铸膜.高分辨率透明掩膜图案用CorelDraw软件绘制并用高分辨率行式打印在塑料片上.制备微结构的聚合物材料为摩尔比85/15的聚乳酸/乙醇酸(PLGA)共聚物,对其进行预处理使之具有适当的硬度和柔韧性.用铸造、旋涂两种成模方法制备形体尺寸为10～100 μm的PLGA肢手架.对影响肢手架结构完整及横向分辨率的因素进行了讨论和优化,并对两种成型方法的横向、纵向分辨率进行了比较.作为脚手架在组织工程上应用的概念验证,用热层压方法制造用于细胞培养的多层聚合物结构.实验结果表明,软刻蚀技术提供了一种实现组织工程微尺度3D聚合物结构的有效工具.     

On-chip fabrication of magnetic alginate hydrogel microfibers by multilayered pneumatic microvalves

Alginate hydrogel has widespread applications in tissue engineering, cancer therapy, wound management and drug/cell/growth factor delivery due to its biocompatibility, hydrated environment and desirable viscoelastic properties. However, the lack of controllability is still an obstacle for utilizing it in the fabrication of 3D tissue constructs and accurate targeting in mass delivery. Here, we proposed a new method for achieving magnetic alginate hydrogel microfibers by dispersing magnetic nanoparticles in alginate solution and solidifying the magnetic alginate into hydrogel fiber inside microfluidic devices. The microfluidic devices have multilayered pneumatic microvalves with hemicylindrical channels to fully stop the fluids. In the experiments, the magnetic nanoparticles and the alginate solution were mixed and formed a uniform suspension. No aggregation of magnetic nanoparticles was found, which is crucial for flow control inside microfluidic devices. By regulating the flow rates of different solutions with the microvalves inside the microfluidic device, magnetic hydrogel fibers and nonmagnetic hydrogel fibers were fabricated with controlled sizes. The proposed method for fabricating magnetic hydrogel fiber holds great potential for engineering 3D tissue constructs with complex architectures and active drug release.     

Creation of a unit block library of architectures for use in assembled scaffold engineering

Guided tissue regeneration is gaining importance in the field of orthopaedic tissue engineering as need and technology permits the development of site-specific engineering approaches. Computer Aided Design (CAD) and Finite Element Analysis (FEA) hybridized with manufacturing techniques such as Solid Freeform Fabrication (SFF), is hypothesized to allow for virtual design, characterization, and production of scaffolds optimized for tissue replacement. However, a design scope this broad is not often realized due to limitations in preparing scaffolds both for biological functionality and mechanical longevity. To aid scientists in fabrication of a successful scaffold, we propose characterization and documentation of a library of micro-architectures, capable of being seamlessly merged according to the mechanical properties (stiffness, strength), flow perfusion characteristics, and porosity, determined by the scientist based on application and anatomic location. The methodology is discussed in the sphere of bone regeneration, and examples of catalogued shapes are presented. Similar principles may apply for other organs as well.     

Optimal design of a 3D-printed scaffold using intelligent evolutionary algorithms

Fabrication of three-dimensional structures has gained increasing importance in the bone tissue engineering (BTE) field. Mechanical properties and permeability are two important requirement for BTE scaffolds. The mechanical properties of the scaffolds are highly dependent on the processing parameters. Layer thickness, delay time between spreading each powder layer, and printing orientation are the major factors that determine the porosity and compression strength of the 3D printed scaffold.In this study, the aggregated artificial neural network (AANN) was used to investigate the simultaneous effects of layer thickness, delay time between spreading each layer, and print orientation of porous structures on the compressive strength and porosity of scaffolds. Two optimization methods were applied to obtain the optimal 3D parameter settings for printing tiny porous structures as a real BTE problem. First, particle swarm optimization algorithm was implemented to obtain the optimum topology of the AANN. Then, Pareto front optimization was used to determine the optimal setting parameters for the fabrication of the scaffolds with required compressive strength and porosity. The results indicate the acceptable potential of the evolutionary strategies for the controlling and optimization of the 3DP process as a complicated engineering problem.     

Functionally heterogeneous porous scaffold design for tissue engineering

Porous scaffolds with interconnected and continuous pores have recently been considered as one of the most successful tissue engineering strategies. In the literature, it has been concluded that properly interconnected and continuous pores with their spatial distribution could contribute to perform diverse mechanical, biological and chemical functions of a scaffold. Thus, there has been a need for reproducible and fabricatable scaffold design with controllable and functional gradient porosity. Improvements in Additive Manufacturing (AM) processes for tissue engineering and their design methodologies have enabled the development of controlled and interconnected scaffold structures. However homogeneous scaffolds with uniform porosity do not capture the intricate spatial internal micro architecture of the replaced tissue and thus are not capable of capturing the design. In this work, a novel heterogeneous scaffold modeling is proposed for layered-based additive manufacturing processes. First, layers are generated along the optimum build direction considering the heterogeneous micro structure of tissue. Each layer is divided into functional regions based on the spatial homogeneity factor. An area weight based method is developed to generate the spatial porosity function that determines the deposition pattern for the desired gradient porosity. To design a multi-functional scaffold, an optimum deposition angle is determined at each layer by minimizing the heterogeneity along the deposition path. The proposed methodology is implemented and illustrative examples are also provided. The effective porosity is compared between the proposed design and the conventional uniform porous scaffold design. Sample designed structures have also been fabricated with a novel micro-nozzle biomaterial deposition system. The result has shown that the proposed methodology generates scaffolds with functionally gradient porosity.     

Internal architecture design and freeform fabrication of tissue replacement structures

Modeling, design and fabrication of tissue scaffolds with intricate architecture, porosity and pore size for desired tissue properties presents a challenge in tissue engineering. This paper will present the details of our development in the design and fabrication of the interior architecture of scaffolds using a novel design approach. The interior architecture design (IAD) approach seeks to generate layered scaffold freeform fabrication tool path without forming complicated 3D CAD scaffold models. This involves: applying the principle of layered manufacturing to determine the scaffold individual layered process planes and layered contours; defining the 2D characteristic patterns of the scaffold building blocks (unit cells) to form the Interior Scaffold Pattern; and the generating the process tool path for freeform fabrication of these scaffolds with the specified interior architecture. Feasibility studies applying the IAD algorithm to example models with multi-interior architecture and the generation of fabrication planning instructions will also be presented.     

Bayesian computer-aided experimental design of heterogeneous scaffolds for tissue engineering

This paper presents a Bayesian methodology for computer-aided experimental design of heterogeneous scaffolds for tissue engineering applications. These heterogeneous scaffolds have spatial distributions of growth factors designed to induce and direct the growth of new tissue as the scaffolds degrade. While early scaffold designs have been essentially homogenous, new solid freeform fabrication (SFF) processes enable the fabrication of more complex, biologically inspired heterogeneous designs with controlled spatial distributions of growth factors and scaffold microstructures. SFF processes dramatically expand the number of design possibilities and significantly increase the experimental burden placed on tissue engineers in terms of time and cost. Therefore, we use a multi-stage Bayesian surrogate modeling methodology (MBSM) to build surrogate models that describe the relationship between the design parameters and the therapeutic response. This methodology is well suited for the early stages of the design process because we do not have accurate models of tissue growth, yet the success of our design depends on understanding the effect of the spatial distribution of growth factors on tissue growth. The MBSM process can guide experimental design more efficiently than traditional factorial methods. Using a simulated computer model of bone tissue regeneration, we demonstrate the advantages of Bayesian versus factorial methods for designing heterogeneous fibrin scaffolds with spatial distributions of growth factors enabled by a new SFF process.     

基于多模态成像技术监测基因修饰支架中血管生成及修复临界性骨缺损的研究

基因修饰促血管化的支架是促进骨再生的有效方法之一,它可以将目的基因转移到内源性细 胞中实现生长因子原位、持续表达,诱导内源性细胞的增殖、迁移和分化,从而促进骨组织再生。该 文以慢病毒介导基因修饰多孔 PLGA/nHAp 复合支架诱导血管生成为研究对象,采用静电吸附和低温冷冻方法制备基因修饰多孔 PLGA/nHAp 复合支架;以小鼠顶骨临界性骨缺损为模型,利用多模态双光子及光声显微成像技术在体、实时、连续监测,研究骨修复过程中基因修饰多孔支架诱导血管化的动态过程。体外实验结果显示,慢病毒颗粒从支架上的持续释放长达 5 天,缓释出的病毒颗粒可以有效转染 293T 细胞并表达 PDGF-BB 因子。体内实验结果表明,慢病毒介导基因修饰多孔 PLGA/nHAp 复合支架,可以实现 PDGF-BB 因子原位表达,促进体内局部及系统性干细胞等细胞迁移,加快血管诱导生成并提高骨缺损部位骨组织的再生能力。同时,在该研究中,成功使用并比较了多模态双光子及光 声显微成像技术在体、实时、连续监测 3D 骨组织支架内血管形成的动态变化过程,并验证了基因修饰对于提高 3D 打印支架的生物学反应性的作用。该研究为研究不同支架对血管生成作用的监测与鉴定提供了新的技术手段。     

骨组织支架的计算机辅助设计方法综述

随着先进的计算机辅助设计和增材制造技术的快速发展,使得制造具有复杂几何结构的骨组织支架成为可能。根据骨组织支架功能设计要求,从几何形态的角度出发将其结构分为规则性多孔结构和不规则多孔结构两大类,并综述了骨组织支架的设计方法,特别强调了两种适合增材制造的设计方法,即三周期极小曲面(TPMS)和拓扑优化。针对骨组织支架结构设计面临的技术挑战,展望了骨组织支架设计方法的可能发展趋势。     

Modeling and simulation of drug delivery from a new type of biodegradable polymer micro-device

In this paper, modeling and simulation of a new type of controlled drug delivery micro-device based on biodegradable polymers is reported. The micro-device consists of micro-chambers arrays for drug storage to achieve linear release. The micro-chambers are fabricated with polyanhydrides (CPP-SA) using the UV-LIGA technology and the controlled release process are the combined results of the design of the micro-chambers and the biodegradable characteristics of the polymer. This type of drug delivery system has some unique advantages in controlled long-term drug delivery, such as larger loading volume than the matrices release systems, easier control for the release rate, etc. It is necessary to optimize the structure for the long-term and zero-order drug release. Based on the Monte Carlo erosion model, the drug release model is founded for the drug delivery system and using the new model, the drug release profiles from the delivery systems with different structures are simulated. The simulated results indicate that the effect of the drug delivery is dependent on the micro-structure of the delivery system and the simulated drug profiles of coaxial rings micro-cavity shape equal to zero-order released model approximatively. The simulated results are very important to the application research of the new biodegradable polymer micro-device.     

Numerical investigation of uniformity of flow distribution in parallel micro-channels with different manifolds and working fluids

Microsystem Technologies - Uniformity of flow distribution is an application subject in many engineering equipment such as in drug delivery and fuel processing reactors. With a uniform distribution...     

Bio-MEMS fabricated artificial capillaries for tissue engineering

In this report, we focus on the microfabrication and cell seeding issues of artificial blood capillaries for tissue engineering. Two different fabrication methods (stainless steel electroforming and silicon electroforming) and a number of materials (PC, Polycarbonate and biocompatible material PLGA, poly lactide-co-glycolides) are implemented to build the vascular network. The vascular network is then used as the scaffold to cultivate the bovine endothelial cell (BEC). During the period of cell cultivation, oxygen and nutrient need to be continuously delivered by a circular pressurizing system. In cell culture, encouraging results are obtained through the dynamical seeding of the BEC on the scaffolds. A systematic cell culture process has been developed after repeated experiments. Successful seeding efficiencies are obtained by using the developed systematic cell culture process.     

Modeling and simulation of drug release from multi-layer biodegradable polymer microstructure in three dimensions

Multi-layer biodegradable polymer drug delivery microstructures with micro-chambers have many exceptional advantages in a long-term controlled drug delivery. In this paper, a mathematical model for the drug release from this type of three-dimensional (3D) drug delivery microstructures is presented by using 3D cellular automata and discrete iterations. The validity of the model is proved by comparing with the Gőpferich’s simulated profiles for the same composite polymer cylinder matrices. Based on this model, furthermore, the simulations are done to describe the dynamic behavior of drug release from this type of microstructures. The simulation results show that this 3D mathematical model can describe accurately the drug release behavior and therefore can provide a new optimal design tool for this kind of multi-layer biodegradable polymer drug delivery microstructure.     

A control approach for pore size distribution in the bone scaffold based on the hexahedral mesh refinement

Tissue engineering is the application of that knowledge to the building or repairing of tissues. Generally, engineered tissue is a combination of living cells and a support structure called scaffolds. Modeling, design and fabrication of tissue scaffold with intricate architecture, porosity and pore size for desired tissue properties presents a challenge in tissue engineering. In this paper, a control approach for pore size distribution in the bone scaffold based on the hexahedral mesh refinement is presented. Firstly, the bone scaffold modeling approach based on the shape function in the finite element method is provided. The resulting various macroporous morphologies can be obtained. Then conformal refinement algorithm for all-hexahedral element mesh is illustrated. Finally, a modeling approach for constructing tissue engineering (TE) bone scaffold with defined pore size distribution is presented. Before the conformal refinement of all-hexahedral element mesh, a 3D mesh with various hexahedral elements must be provided. If all the pores in the bone scaffold need to be reduced, that means that the whole hexahedral mesh needs to be refined. Then the solid entity can be re-divided with altered subdivision parameters. If the pores in the local regions of bone need to be reduced, that means that 3D hexahedral mesh in the local regions needs to be refined. Based on SEM images, the pore size distribution in the normal bone can be obtained. Then, according to the conformal refinement of all-hexahedral element meshes, defined hexahedral size distribution can be gained, which leads to generate defined pore size distribution in the bone scaffold, for the pore morphology and size are controlled by various subdivided hexahedral elements. Compared to other methods such as varying processing parameters in supercritical fluid processing and multi-interior architecture design, the method proposed in this paper enjoys easy-controllability and higher accuracy.     

The optimization of hybrid scaffold fabrication process in precision deposition system using design of experiments

In recent tissue engineering field, it is being reported that the fabrication of three-dimensional (3D) scaffolds having high porous and controlled internal/external architectures can give potential contributions in cell adhesion, proliferation and differentiation. To fabricate these scaffolds, various rapid prototyping technologies are being applied to. The rapid prototyping technology has made it possible to fabricate solid free-form 3D microstructures in layer-by-layer process. In this research, we introduce the development of precision deposition system, which is one of rapid prototyping technologies, and the fabrication result of scaffold using design of experiments (DOE) to optimize the deposition process. The precision deposition system required the combination of several technologies, including motion control, thermal control, pneumatic control, and CAD/CAM software. Through the organization of experimental approach using DOE, the fabrication process of hybrid scaffold, which is composed of blended poly-caprolactone, poly-lactic-co-glycolic acid and tricalcium phosphate, is established to get a uniform line width, line height and porosity efficiently.     

基于Monte Carlo模型的微型PLGA给药系统建模及仿真

多腔体的微型可降解高分子聚合物PLGA药物缓释系统是一种新型植入式给药微器件,其载体结构是结合药物释放的要求和高分子聚合物生物降解特性进行设计并利用MEMS工艺制备.为了解微型给药系统实际释药的性能,需要对其进行建模和仿真研究.基于体溶蚀的Monte Carlo溶蚀模型,建立了具有多腔体的微型PLGA给药载体的释药模型,并对腔体结构为圆形的微型给药系统进行了释药过程仿真.仿真结果表明本文建立的微系统释药模型可以较为准确的描述微系统的释药过程,仿真模型对进一步开发微型PLGA给药系统有重要的参考价值.     

Integrated microfluidic drug delivery devices: a component view

Research on drug delivery devices is progressing rapidly with the main objective being the delivery of precise quantity of drugs into the target area of the body. A drug delivery device (DDD) needs to accurately control the flow rate of drug delivery and protects the body from undesired additional doses. An integrated microfluidic drug delivery device (IMDDD) is a miniature device that can regulate and monitor the delivery of the right amount of drug using micro-scale components. IMDDDs offer several advantages including ease of use, electro-chemical controllability, low power consumption, simplicity, fast fabrication, and good bio-compatibility. Various IMDDDs have been developed for treatment of cancer, cardiovascular disorder, eye and brain diseases, stress, and diabetes. This paper presents a generic architecture for IMDDDs, discusses the existing drug delivery methods, summarizes the specifications of the components, and identifies a number of performance evaluation parameters. The operation of IMDDDs is presented through fourteen potential internal components. In addition, recommendations on how enhance the design and fabrication process of IMDDDs are given.