Continuum Modeling and Simulation in Bone Tissue Engineering

Bone tissue engineering is currently a mature methodology from a research perspective. Moreover, modeling and simulation of involved processes and phenomena in BTE have been proved in a number of papers to be an excellent assessment tool in the stages of design and proof of concept through in-vivo or in-vitro experimentation. In this paper, a review of the most relevant contributions in modeling and simulation, in silico, in BTE applications is conducted. The most popular in silico simulations in BTE are classified into: (i) Mechanics modeling and sca old design, (ii) transport and flow modeling, and (iii) modeling of physical phenomena. The paper is restricted to the review of the numerical implementation and simulation of continuum theories applied to di erent processes in BTE, such that molecular dynamics or discrete approaches are out of the scope of the paper. Two main conclusions are drawn at the end of the paper: First, the great potential and advantages that in silico simulation o ers in BTE, and second, the need for interdisciplinary collaboration to further validate numerical models developed in BTE.Ministerio de Economía y Competitividad del Gobierno España DPI2017-82501-

MODELLING AND IN VIVO MONITORING OF THE TIME DEPENDENT MECHANICAL PROPERTIES OF TISSUE ENGINEERING SCAFFOLDS

When organs and tissue fail either due to pre-existing disease progression or by accidental damage, current state of the art treatment involves the replacement of the damaged or diseased tissue with new donor derived organs/tissue. The limitations of these current approaches include a limited supply of tissue for treatments and the immune response of the patient’s own body against the new implanted tissue/organs. To solve these issues, tissue engineering aims to develop artificial analogs derived from a patient’s own cells instead of donor tissue/organs for treatment. To this end, a promising approach, known as scaffold-based tissue engineering, is to seed engineered constructs or scaffolds with cells to form artificial analogs, which then develop with time into new tissue/organs for implantation. The mechanical properties of the scaffold play a critical role in the success of scaffold-based treatments, as the scaffold is expected to provide a temporary support for the generation of new tissue/organs without causing failure at any time during the treatment process. It is noted that due to the degradation of scaffold in the treatment process, the mechanical properties of the scaffold are not constant but change with time dynamically. This raises two scientific issues; one is the representation of the time-dependent mechanical properties and the other one is the monitoring of these properties, especially in the in vivo environments (i.e., upon the implantation of scaffolds into animal/patient bodies). To address these issues, this research is aimed at performing a novel study on the modelling and in vivo monitoring of the time dependent mechanical properties of tissue engineering scaffolds. To represent the time-dependent mechanical properties of a scaffold, a novel model based on the concept of finite element model updating is developed. The model development involves three steps: (1) development of a finite element model for the effective mechanical properties of the scaffold, (2) parametrizing the finite element model by selecting parameters associated with the scaffold microstructure and/or material properties, which vary with scaffold degradation, and (3) identifying selected parameters as functions of time based on measurements from the tests on the scaffold mechanical properties as they degrade. To validate the developed model, scaffolds were made from the biocompatible polymer polycaprolactone (PCL) mixed with hydroxyapatite (HA) nanoparticles and their mechanical properties were examined in terms of the Young modulus. Based on the bulk degradation exhibited by the PCL/HA scaffold, the molecular weight was selected for model updating. With the identified molecular weight, the finite element model v developed was effective for predicting the time-dependent mechanical properties of PCL/HA scaffolds during degradation . To monitor and characterize scaffold mechanical properties in vivo, novel methods based on synchrotron-based phase contrast imaging and finite element modeling were developed. The first method is to represent the scaffold mechanical properties from the measured deflection. In this method, the phase contrast imaging is used to characterize the scaffold deflection caused by ultrasound radiation forces; and the finite element modelling is used to represent the ultrasonic loading on the scaffold, thus predicting the mechanical properties from the measured deflection. The second method is to characterize the scaffold degradation due to surface erosion, which involves the remote sensing of the time dependent morphology of tissue scaffolds by phase contrast imaging and the estimation of time dependent mass loss of the scaffolds from the sensed morphology. The last method is to relate the elastic mechanical property and nonlinear stress-strain behavior to the scaffold geometry, both changing with time during surface erosion. To validate the above methods, scaffolds was made from varying biomaterials (PLGA and PCL) and their mechanical properties (degradation, mass loss, and elastic modulus) were examined experimentally. The results obtained illustrate the methods developed in this research are effective to monitor and characterize scaffold mechanical properties. The significance of this research is that the model developed for the scaffold mechanical properties can be used in the design of scaffolds with the desired mechanical properties, instead of the trial and error methods typical in current scaffold design; and that these novel monitoring methods based on synchrotron imaging can be used to characterize the scaffold time-dependent mechanical properties in the in vivo environments, representing an important advance in tissue engineering

Effect of mechanical stimulation on the degradation of poly(lactic acid) scaffolds with different designed structures

Biodegradability is one of the required scaffold functions for bone tissue engineering, and it is influenced by the mechanical micro-environment after scaffold implantation into body. This paper aimed to develop a mathematical model to numerically study the mechanical impact on the degradation of poly (lactic acid) (PLA) scaffolds with different designed structures. In addition, the diffusion-governed autocatalysis on the scaffold degradation was also included, and the scaffold collapse time by an author-developed algorithm was determined. The results showed that an increase in mechanical stimulation led to an increase in the scaffold degradation rate. Moreover, different structures with a similar porosity shared a degradation tendency but had different collapse times, which was very sensitive to the diffusion coefficient of the scaffold. The present study could be helpful to understand the dynamic degradation process of PLA scaffolds, and guide the design of PLA material and scaffold structure. It may be also used as a tool for the evaluation of the in vitro and in vivo degradation performance of scaffolds.</p

Identifying Performance Criteria of Fully Bioresorbable Scaffolds for Endovascular Applications

Background: Bioresorbable scaffolds (BRS) have revolutionized percutaneous coronary intervention in clinical cardiovascular medicine. As opposed to permanent alternatives such as metallic stents, BRS have an inherent potential to reduce the occurrence of untoward events such as vessel re-narrowing or thrombosis by virtue of undergoing complete and controlled resorption post- implantation. While BRS platforms demonstrate a clear potential to mitigate risk stemming from incomplete vessel healing, they introduce a new set of considerations to clinical safety and efficacy. Foremost among these issues is the fate of and biological response to material by-products that evolve throughout the scaffold degradation and erosion processes, motivating a comprehensive assessment of how material design and deployment parameters impact scaffold performance in the arterial environment. Dissertation summary: The overall goal of this project is to identify performance criteria of BRS for endovascular applications. First, we develop a computational model to predict scaffold by-product generation and release throughout the tissue healing process. Parametric studies are used to elucidate the material and deployment parameters which most significantly modulate by-product fate and thus patient risk. We next perform an array of in vitro studies to understand how BRS fracture risk depends on the expansion ratio imparted at implantation. Due to the inherent potential for fracture during endovascular delivery, BRS over expansion is a more serious concern as compared to analogous deployment of metallic stents. Conversely, under expansion increases the risk of thrombosis due to an alteration of in situ geometry and concomitant disturbance of arterial blood flow. To gain insight on the effects of scaffold expansion, computational studies are complemented by in vitro measures of BRS erosion, degradation, radial strength, and drug delivery kinetics under plausible alterations of the degree of expansion. Finally, a dynamic flow system which mimics arterial blood flows is developed and used to study the effects of the specific implantation site on BRS performance. Taken together, the studies encompassed in this dissertation provide an efficient means for iterative evaluation of candidate scaffolds as well as the basis to optimize material design and delivery strategies as this technology continues to evolve

Development of multifunctional hybrid scaffolds for massive bone defects filling and regeneration

Despite the growing number of survival cases, due to the increase in cases, the death rate from cancer-related diseases has been increasing over the years. Being less than 0.2% of all cancers, primary bone cancers are extremely unusual and often curable. However, about 50% of these tumors can metastasize, so early intervention is frequently necessary. Tumor or tumor-like resection derived from osteosarcoma usually leads to the creation of large bone defects, which constitute a reconstructive problem. The current standard procedures used to resolve this and other related issues are viable solutions. However, they are far from being ideal, still carrying many risks, and often failing. With the ongoing advances in a variety of theoretical subjects and in manufacturing (namely 3D printing), bone graft substitutes using smart biodegradable scaffolds are revolutionizing bone tissue engineering and regenerative medicine. In addition, despite the numerous options currently available, the scientific consensus is that the ideal bone graft should likely have a hybrid composition. The goal of this thesis is to provide an overall review of the current state-of-the-art on the main concepts associated with chitosan-based 3D scaffolds. Porous scaffolds produced by conventional fabrication techniques, using chemically cross-linked chitosan hydrogel are analysed. Due to its growing popularity, cross-linking agent genipin was selected as a case study. Follows an analysis on the most recent methods of scaffold fabrication reinforced by rapid prototyping techniques (PLA is further examined as printing material). The incorporation of bioactive agents and cells is evaluated in both options. The different factors that influence the properties of each material, the overall performance of the 3D structures, and the most common methods of surface modification are also discussed topics. To finalize, the key aspects that still need improvement and future perspectives for scaffold technology are highlighted.Representando menos de 0,2% de todos os casos de cancro, os cancros ósseos primários são extremamente incomuns e, na maioria das vezes, curáveis, no entanto, cerca de 50% destes tumores podem metastizar e, portanto, uma intervenção precoce é frequentemente necessária. A ressecção de tumores ou de variantes destes geralmente leva à criação de grandes defeitos ósseos que constituem um problema reconstrutivo. Os procedimentos padrões usados atualmente para resolver este e outros problemas relacionados são soluções viáveis, no entanto, ainda longe de serem ideais, constatando-se a presença de diversos riscos e de um elevado rácio de insucesso. Com os contínuos avanços nos demais conteúdos teóricos e em fabricação (nomeadamente impressão 3D), os substitutos de scaffolds (“andaimes”) ósseos recorrendo a suportes biodegradáveis inteligentes têm vindo a revolucionar a engenharia de tecidos ósseos e a medicina regenerativa. Para além disso, apesar das mais diversas opções atualmente disponíveis, o consenso científico é que o scaffold ideal deverá ter uma composição híbrida. Esta tese pretende fornecer uma revisão geral do estado da arte atual acerca dos principais conceitos associados a scaffolds 3D à base de quitosano. São analisados scaffolds porosos produzidos por técnicas convencionais, à base de hidrogel de quitosano reticulado quimicamente. Devido à sua crescente popularidade, o agente de reticulação genipina foi selecionado como estudo de caso. Segue se uma análise relacionada com os métodos mais recentes de fabrico de scaffoldsreforçados por técnicas de prototipagem rápida (PLA é posteriormente examinado como material de impressão). A incorporação de agentes bioativos e células é avaliada em ambas as opções. Os diferentes fatores que influenciam as propriedades de cada material, o desempenho geral da estrutura 3D e os métodos mais comuns de preparação de superfície são também tópicos discutidos. Para finalizar, destacam-se os aspetos ainda sujeitos a aperfeiçoamento e as perspetivas futuras para a tecnologia de scaffolds

The interplay between tissue growth and scaffold degradation in engineered tissue constructs

In vitro tissue engineering is emerging as a potential tool to meet the high demand for replacement tissue, caused by the increased incidence of tissue degeneration and damage. A key challenge in this field is ensuring that the mechanical properties of the engineered tissue are appropriate for the in vivo environment. Achieving this goal will require detailed understanding of the interplay between cell proliferation, extracellular matrix (ECM) deposition and scaffold degradation.\ud \ud In this paper, we use a mathematical model (based upon a multiphase continuum framework) to investigate the interplay between tissue growth and scaffold degradation during tissue construct evolution in vitro. Our model accommodates a cell population and culture medium, modelled as viscous fluids, together with a porous scaffold and ECM deposited by the cells, represented as rigid porous materials. We focus on tissue growth within a perfusion bioreactor system, and investigate how the predicted tissue composition is altered under the influence of (i) differential interactions between cells and the supporting scaffold and their associated ECM, (ii) scaffold degradation, and (iii) mechanotransduction-regulated cell proliferation and ECM deposition.\ud \ud Numerical simulation of the model equations reveals that scaffold heterogeneity typical of that obtained from μCT scans of tissue engineering scaffolds can lead to significant variation in the flow-induced mechanical stimuli experienced by cells seeded in the scaffold. This leads to strong heterogeneity in the deposition of ECM. Furthermore, preferential adherence of cells to the ECM in favour of the artificial scaffold appears to have no significant influence on the eventual construct composition; adherence of cells to these supporting structures does, however, lead to cell and ECM distributions which mimic and exaggerate the heterogeneity of the underlying scaffold. Such phenomena have important ramifications for the mechanical integrity of engineered tissue constructs and their suitability for implantation in vivo

Segajuhtelektroodide mikrostruktuuri ja keemilise koostise mõju pööratava funktsionaalsusega tahkeoksiidsete kütuseelementide elektrokeemilisele käitumisele

Väitekirja elektrooniline versioon ei sisalda publikatsiooneTulenevalt ühiskonna üha suurenevast energianõudlusest otsitakse järjest efektiivsemaid energia muundamis- ja salvestamisseadmeid. Arendussuundi on mitmeid. Neist kõrgeima elektrilise efektiivsusega elektri- ja soojusenergia koostootmisvõimalust pakub pööratava funktsionaalsusega tahkeoksiidne kütuseelement. Kütuseelemendina töötades võimaldab nimetatud süsteem efektiivset elektrienergia tootmist erinevatest kütustest, nagu vesinik, süsivesinikud, alkoholid, sünteesgaas jpt. Elektrolüüsirežiimis on võimalik ülejäävat elektrienergiat salvestada erinevatesse keemilistesse ühenditesse, nagu vesinik ja süsinikmonooksiid. Mainitud tehnoloogia kommertsialiseerimise suurimad väljakutsed on aga seotud materjalide stabiilsuse ja süsteemi valmistamise liiga kõrge hinnaga. Kommertisaliseerimiseelses faasis olevates süsteemides kasutatavate metall-keraamiliste elektroodide puudusteks on ka halb redokstsüklite taluvus ning katalüütiliselt aktiivsete metalliosakeste ümberkristalliseerumine, aga ka süsiniku sadenemisest ning väävlist tingitud aktiivsuse vähenemine. Mitmetele nimetatud probleemidele võiks leevendust pakkuda redoksstabiilsed täiskeraamilised segajuhtelektroodid. Sellised materjalid on hea taluvusega väävli suhtes, aga oluliselt madalama elektrokeemilise aktiivsusega. Käesoleva doktoritöö raames uuriti uudsete täiskeraamiliste segajuhtanoodide aktiveerimise võimalusi läbi keemilise koostise muutmise, aga ka kasutades pinna aktiveerimist katalüütiliselt aktiivsete nanoosakeste väljalahustamisel elektroodi faasist. Uuriti elektroodi mikrostruktuuri mõju ühikraku elektrokeemilisele aktiivsusele ning karakteriseeriti kõige aktiivsemat elektroodimaterjali H2O ja CO2 kaaselektrolüüsirežiimis. Leiti, et materjalide elektrokeemiline aktiivsus on keeruline kombinatsioon kompleksoksiidi ioonse-, elektroonse juhtivuse aga ka pinna katalüütilise aktiivsuse komponentidest. Samuti näidati elektroodimaterjali hulga optimeermise olulisust erineva keemilise koostisega anoodimaterjalide korral. Parimat elektrokeemilist aktiivsust nii kütuseelemendi režiimis 0.5 V (1.08 A/cm2) kui ka elektrolüüsi režiimis 1.6 V juures (-1.37 A/cm2) näitas pallaadiumi ja tseeriumoksiidi nanoosakestega aktiveeritud La0.8Sr0.2Cr0.5Mn0.5O3-δ materjal.Due to increasing energy demand, the implementation of renewable energy resources is an urgent need. A most important step toward this goal is to develop efficient, environmentally friendly devices for sustainable energy conversion and storage. One of such technologies is reversible solid oxide cell (RSOC), which can work as high-temperature solid oxide fuel cell (SOFC) for fuel oxidation and as solid oxide electrolysis cell (SOEC) for fuel production from excess electricity and steam or carbon dioxide. The advantage of mentioned systems is high electrical and overall efficiency as well as fuel flexibility. However, research and development are still needed to improve reliability, lifetime, and lower the cost of the systems. The most commonly used anode materials for SOCs are metal-ceramic (cermet) composites, which are very sensitive to the redox cycles, catalyst recrystallization, carbon deposition, and sulfur impurities under standard working conditions. Alternatively, mixed ionic-electronic conductive (MIEC) materials have been in focus during the last years as a more stable alternative for cermet materials. So far, low catalytic activity and poor conductivity are still the most common throwbacks for MIEC electrodes, and therefore, additional activation of materials is necessary. In this work, activation of several potential MIEC materials was investigated through the modifications in the chemical composition or through the infiltration of catalyst nanoparticles. The influence of electrode microstructure on the electrochemical activity was also studied, and the most active material was characterized in H2O and CO2 co-electrolysis mode. The electrochemical activity of MIEC materials was found to be a complex combination of the electronic-, ionic - and surface catalytic properties of the used oxide. Finally, the importance of optimal electrode material loading in the case of different materials was demonstrated. Best electrochemical activity in fuel cell (1.08 A/cm2 at 0.5 V) and electrolysis (-1.37 A/cm2) modes was demonstrated by Pd and CeO2 infiltrated La0.8Sr0.2Cr0.5Mn0.5O3-δ.https://www.ester.ee/record=b530261

Effect of rehabilitation exercise durations on the dynamic bone repair process by coupling polymer scaffold degradation and bone formation

Implantation of biodegradable scaffold is considered as a promising method to treat bone disorders, but knowledge of the dynamic bone repair process is extremely limited. In this study, based on the representative volume cell of a periodic scaffold, the influence of rehabilitation exercise duration per day on the bone repair was investigated by a computational framework. The framework coupled scaffold degradation and bone remodeling. The scaffold degradation was described by a function of stochastic hydrolysis independent of mechanical stimulation, and the bone formation was remodeled by a function of the mechanical stimulation, i.e., strain energy density. Then, numerical simulations were performed to study the dynamic bone repair process. The results showed that the scaffold degradation and the bone formation in the process were competitive. An optimal exercise duration per day emerged. All exercise durations promoted the bone maturation with a final Young's modulus of 1.9 ± 0.3 GPa. The present study connects clinical rehabilitation and fundamental research, and is helpful to understand the bone repair process and further design bone scaffold for bone tissue engineering

Covalently Crosslinked Organic/Inorganic Hybrid Biomaterials for Bone Tissue Engineering Applications

Scaffolds are key components for bone tissue engineering and regeneration. They guide new bone formation by mimicking bone extracellular matrix for cell recruitment and proliferation. Ideally, scaffolds for bone tissue engineering need to be osteoconductive, osteoinductive, porous, degradable and mechanically competent. As a single material can not provide all these requirements, composites of several biomaterials are viable solutions to combine various properties. However, conventional composites fail to fulfil these requirements due to their distinct phases at the microscopic level. Organic/inorganic (O/I) class II hybrid biomaterials, where the organic and inorganic phases are chemically crosslinked on a molecular scale, hence the phases are homogenously dispersed, are the ideal choices for bone tissue engineering. In this research, polycaprolactone/borophosphosilicate glass (PCL/BPSG) and poly(vinylpyrrolidone-co-triethoxyvinylsilane)/bioactive glass (Poly(VP-co-TEVS)/BG) class II hybrid biomaterials were successfully prepared via a sol-gel process. PCL was functionalized with 3-glycidoxypropyl trimethoxysilane at both ends prior to hybrid syntheses. Trimethoxysilane-functionalized PCL was then polycondensed with the glass precursors via non-aqueous sol gel reactions to form covalently bonded O/I network with -C-Si-O-Si- bonds. The resultant amorphous and transparent hybrid materials exhibited apatite depositions when incubated with simulated body fluid. The ultimate compressive stress, modulus and toughness of these hybrids were significantly greater compared with their conventional composites counterparts, attributed to the covalent bonding between the O/I phases. In addition, these hybrids exhibited more controlled degradation and subsequent ion release without showing any abrupt features. Pre-osteoblast cells seeded on the hybrid biomaterials displayed enhanced spreading, focal adhesion formation, and cell number, indicating cytocompatibility. PCL/BPSG hybrid scaffolds were prepared by a solvent-free casting and particulate leaching methods to obtain consistent pore size distribution, controllable porosity and pore interconnectivity. Significant number of cell infiltration and adhesion into the scaffolds were observed in cell culture conditions. Bone-associated gene expression by induced pluripotent stem cells on these scaffolds revealed that the hybrid scaffolds had an upregulating effect on gene expressions for alkaline phosphatase, osteopontin and osteocalcin

Development and in vitro characterization of three dimensional biodegradable scaffolds for peripheral nerve tissue engineering

Tissue engineering emerges nowadays to seek new solutions to damaged tissues and/or organs by replacing or repairing them with engineered constructs or scaffolds. In nerve tissue engineering, scaffolds for the repair of peripheral nerve injuries should act to support and promote axon growth following implantation. It is believed that substantial progress can be made by creating scaffolds from biomaterials, with growth-promoting molecules and spatially-controlled microstructure. To this end, this research aims to develop three dimensional (3D) scaffolds for peripheral nerve tissue regeneration by focusing on studies on the axon guidance, development and characterization of a novel 3D scaffold, and visualization of scaffolds by means of synchrotron-based diffraction enhanced imaging (DEI). Axon guidance is one of crucial considerations in developing of nerve scaffolds for nerve regeneration. In order to study the axon guidance mechanism, a two dimensional (2D) grid micropatterns were created by dispensing chitosan or laminin-blended chitosan substrate strands oriented in orthogonal directions; and then used in the in vitro dorsal root ganglion (DRG) neuron culture experiments. The results show the effect of the micropatterns on neurite directional growth can preferentially grow upon and follow the laminin-blended chitosan pathways. A novel 3D scaffold was developed for potential applications to peripheral nerve tissue engineering applications. The scaffolds were fabricated from poly L-lactide (PLLA) mixed with chitosan microspheres (CMs) by using a rapid freeze prototyping (RFP) technique, allowing for controllable scaffold microstructure and bioactivities protein release. The scaffold characterization shows that (1) the mechanical properties of the scaffolds depend on the ratio of CMs to PLLA as well as the cryogenic temperature and (2) the protein release can be controlled by adjusting the crosslink degree of the CMs and prolonged after the CMs were embedded into the PLLA scaffolds. Also, the degradation properties of the scaffolds were investigated with the results showing that the addition of CMs to PLLA can decrease the degradation rate as compared to pure PLLA scaffolds. This allows for another means to control the degradation rate. Visualization of polymer scaffolds in soft tissues is challenging, yet essential, to the success of tissue engineering applications. The x-ray diffraction enhanced imaging (DEI) method was explored for the visualization of the PLLA/CMs scaffolds embedded in soft tissues. Among various methods examined, including conventional radiography and in-line phase contrast imaging techniques, the DEI was the only technique able to visualize the scaffolds embedded in unstained muscle tissue as well as the microstructure of muscle tissue. Also, it has been shown that the DEI has the capacity to image the scaffolds in thicker tissue, and reduce the radiation doses to tissues as compared to conventional radiography. The methods and results developed/obtained in this study represent a substantial progress in the development and characterization of 3D scaffolds. This progress forms a basis for the future tests on the scaffolds as applied for peripheral nerve injuries