Osteoarthritis is a degenerative joint disease characterized by painful, progressive articular cartilage lesions that deteriorate joint function. It remains leading cause of disability in the United States, affecting nearly 30 million Americans with increasing prevalence in the aging population, which has resulted in an annual economic burden of $128 billion. Symptomatic, full thickness cartilage injuries often require surgical intervention, because the tissue is predominantly avascular and thus has a limited self-healing capacity. However, clinical management strategies including matrix-induced autologous chondrocyte implantation and osteochondral grafting are inadequate in the long-term due to poor integration of cartilage grafts with surrounding host cartilage and subchondral bone. In addition to physical congruence between graft and host cartilage, a structural or chemically functional barrier that limits osseous invasion into the cartilage compartment is critical in order to maintain the integrity of repaired cartilage. Given these significant clinical challenges, the objective of this thesis is to establish design principles for homotypic and heterotypic tissue integration via a cup-shaped fibrous scaffold system that encapsulates cartilage grafts (autologous or engineered), and integrates them simultaneously with host cartilage and bone at their respective interfaces. Additionally, to facilitate clinical translation of the scaffold cup, an innovative “green electrospinning” method is developed using FDA Q3C Class 3 solvents with minimal manufacturing impact on the environment. It is hypothesized that, to fuse cartilage grafts with host cartilage, the walls of the envisioned cup can direct cell migration directly to the graft-host cartilage interface via chemotactic agent delivery, where scaffold electroactivity will encourage cells to deposit a structurally contiguous neocartilage matrix. At the boundary between the graft and underlying bone, the scaffold cup base will mimic the topography and ceramic chemistry of the native osteochondral interface while preventing bone vasculature from growing upwards into the cartilage, guided by the hypothesis that this will enable the formation of a calcified cartilage interface layer that merges the graft and subchondral bone. To test these hypotheses, this thesis began with green electrospinning the scaffold cup walls incorporated with insulin-like growth factor 1 (IGF-1), a well-established chondrocyte chemoattractant that induced cell migration from cartilage autografts towards resulting fibers. Additionally, the walls contained an optimized dose of graphite nanoparticles to impart electroactivity to the fibers. Mimicking the fixed charge density of cartilage in this way promoted chondrocyte proliferation and biosynthesis of a hyaline cartilage-like matrix in vitro, with selective regulation of proteoglycans (biglycan and decorin) and downregulation of collagen type I compared to a graphite-free fiber control. Moreover, the graphite fibers sequestered IGF-1, sustaining release of the growth factor and improving functional graft-cartilage shear integration strength in vitro. In a full thickness defect osteochondral construct repaired with the scaffold cup and implanted subcutaneously in rat dorsi, localized IGF-1 delivery promoted graft-host cartilage interface matrix elaboration with significantly greater integration strength measured with graphite in the cup walls. For integration with subchondral bone, design criteria for the scaffold cup base were set by quantitatively mapping the compositional and morphometric characteristics of healthy and osteoarthritic human osteochondral tissues, and evaluating FEBio simulations of calcified cartilage and polymer-ceramic composite fibers in silico. These analyses established the need for an interdigitating mesh topography and ceramic particle incorporation, which minimize shear and distribute loading across the fibers, respectively, recapitulating the osteochondral interface’s force gradient from cartilage to bone in order to functionally integrate the tissues. Thus, the dose of calcium deficient apatite (CDA) nanoparticles, which capture the high calcium-phosphate ratio and semi-crystalline atomic structure of native bone mineral, was optimized to promote deep zone chondrocyte growth and biosynthesis of a calcified cartilage matrix in vitro. Moreover, CDA enhanced remodeling of the interface in vivo, with undulating fibers preventing osseous upgrowth. Taken together, these findings delineate the importance of strategic biomimicry in scaffold design, specifically with regards to interface regeneration and cartilage integration. The proposed approach is unique in that it utilized cell homing and an electroactive substrate to mimic properties of the cartilage matrix, with a strategy for simultaneous graft integration with host cartilage and bone. Moreover, the cup design is readily adaptable to current cartilage repair techniques including press-fit autografting and cell-based graft implantation, as well as emerging tissue engineered grafting strategies. Beyond cartilage repair, the scaffold design criteria established in this thesis are broadly applicable to integrating other complex tissue systems, and may inform the regeneration of critical soft-soft (muscle-tendon) and soft-hard (tendon- or ligament-bone) interfaces in the musculoskeletal system.

Orientador: Gustavo Franco Barbosa / Resumo: O desempenho de tecidos e órgãos de todo organismo vivo, fica naturalmente comprometido com o passar dos anos, e se faz necessário intervenções médicas para eventuais reconstituições ou reparações de tecidos acometidos e danificados por doenças ou lesões. Neste contexto, a Engenharia Tecidual tem trabalhado de maneira interdisciplinar nos campos das Engenharias, Biologia e Medicina, e tem trazido grandes evoluções e opções aos já difundidos transplantes e enxertos ósseos. Nesse âmbito, impulsionado pelas recentes aplicações da tecnologia da manufatura aditiva, novos polímeros termoplásticos biodegradáveis têm sido utilizados com sucesso. Dessa forma, este trabalho de pesquisa tem como propósito principal desenvolver scaffolds 3D mimetizando o osso trabecular, aliando as propriedades de biocompatibilidade e biodegradabilidade do já difundido e certificado PLA (ácido polilático). Assim, os scaffolds 3D de PLA em sua versão comercial, são recobertos com látex natural extraído da Hevea brasiliensis por meio da técnica dip-coating, afim de otimizar a biocompatibilidade, promovendo condições para a angiogênese e proporcionando condições para a migração, diferenciação e proliferação de tecido ósseo, características estas que foram detectadas em estudos recentes deste material com resultados promissores. Com auxílio de softwares CAD, foi possível desenvolver geometrias com interconectividade estruturada, seguidos de definição de parâmetros de processamento e fabricação utilizando a t... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Indiana University-Purdue University Indianapolis (IUPUI) / This study represents a cost-effective method to advance the physical and mechanical properties of carbon fiber-reinforced polymer (CFRP) prepreg composite materials, where electrospun multiwalled carbon nanotubes (CNTs)/epoxy nanofibers fabricated and deposited in between the layers of traditional CFRP prepreg composite. CNT-aligned epoxy nanofibers were uniformly formed by an optimized electrospinning method. Electrospinning is considered one of the most flexible, low-cost, and globally recognized methods for generating continuous filaments from submicron to tens of nanometer diameter. Nanofilaments were incorporated precisely on the layers of prepreg to accomplish increased adhesion and interfacial bonding, leading to increased strength and enhancements in more mechanical properties. As a result, the modulus of the epoxy and CNT/epoxy nanofibers were revealed to be 3.24 GPa and 4.84 GPa, leading to 49% enhancement. Furthermore, interlaminar shear strength (ILSS) and fatigue performance at high-stress regimes improved by 29% and 27%, respectively. Barely visible impact damage (BVID) energy improved considerably by up to 45%. The thermal and electrical conductivities were also increased considerably because of the highly conductive CNT networks present in between the CFRP layers. The newly introduced approach was able to deposit high content uniform CNTs at the ply interface of prepregs to enhance the CFRP properties, that has not been achieved in the past because of the randomly oriented high viscosity CNTs in epoxy resins.

This study represents a cost-effective method to advance the physical and mechanical properties of carbon fiber-reinforced polymer (CFRP) prepreg composite materials, where electrospun multiwalled carbon nanotubes (CNTs)/epoxy nanofibers fabricated and deposited in between the layers of traditional CFRP prepreg composite. CNT-aligned epoxy nanofibers were uniformly formed by an optimized electrospinning method. Electrospinning is considered one of the most flexible, low-cost, and globally recognized methods for generating continuous filaments from submicron to tens of nanometer diameter. Nanofilaments were incorporated precisely on the layers of prepreg to accomplish increased adhesion and interfacial bonding, leading to increased strength and enhancements in more mechanical properties. As a result, the modulus of the epoxy and CNT/epoxy nanofibers were revealed to be 3.24 GPa and 4.84 GPa, leading to 49% enhancement. Furthermore, interlaminar shear strength (ILSS) and fatigue performance at high-stress regimes improved by 29% and 27%, respectively. Barely visible impact damage (BVID) energy improved considerably by up to 45%. The thermal and electrical conductivities were also increased considerably because of the highly conductive CNT networks present in between the CFRP layers. The newly introduced approach was able to deposit high content uniform CNTs at the ply interface of prepregs to enhance the CFRP properties, that has not been achieved in the past because of the randomly oriented high viscosity CNTs in epoxy resins.

Orientador: Antonio Carlos Guastaldi / Resumo: O desenvolvimento de biomateriais para a regeneração de tecidos é de grande importância e sua demanda aumenta a cada dia, devido ao aumento do envelhecimento da população, da expectativa e qualidade de vida, bem como ao aumento das taxas de acidentes (trânsito e violência). Os Scaffolds são uma estrutura tridimensional, projetada para suportar infiltração, crescimento e diferenciação celular, a fim de melhorar o desenvolvimento e a formação de novos tecidos. Muitos biomateriais podem ser usados para fabricar essas estruturas, como as biocerâmicas e biopolímeros. No entanto, poucos estudos foram realizados para avaliar sua contaminação microbiológica e a influência dos métodos de esterilização podem ter sobre a estrutura e propriedades dos implantes. Dessa forma, o objetivo deste trabalho foi avaliar as propriedades mecânicas, físico-químicas e microbiológicas, antes e após três métodos de esterilização. Esses Scaffolds foram feitos de celulose bacteriana, alginato de sódio e fosfato de cálcio amorfo. Os Scaffolds foram elaborados mediante processo de liofilização. Eles foram divididos em quatro grupos: um grupo controle e três diferentes métodos de esterilização (esterilização a vapor, esterilização por irradiação ultravioleta e esterilização por micro-ondas). O número de colônias viáveis (UFC/mL) foi obtido através do plaqueamento das amostras em Ágar Dextrose Sabouraud com Cloranfenicol (SDA), Ágar Infusão Cérebro e Coração (BHI), Chromagar e Ágar Sangue. Todos os experimen... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The development of biomaterials for the regeneration of tissues is of great importance and their demand increases every day, due to the increase of the aging population, of the expectation and quality of life, as well as the increase of the accident rates (traffic and violence). Scaffolds are a three-dimensional structure designed to withstand cellular infiltration, growth and differentiation in order to improve the development and formation of new tissues. Many biomaterials can be used to make these structures, such as bioceramics and biopolymers. However, few studies have been conducted to evaluate its microbiological contamination and the influence of sterilization methods may have on the structure and properties of implants. Thus, the aim of this work was to evaluate the mechanical, physicochemical and microbiological properties of Scaffolds, before and after three different sterilization methods. These Scaffolds were made of bacterial cellulose, sodium alginate and amorphous calcium phosphate. Scaffolds were made by lyophilization process. They were divided into four groups: a control group and three different sterilization techniques (steam sterilization, sterilization by ultraviolet irradiation and microwave sterilization). The number of viable colonies (CFU/mL) was obtained by plating the samples in Sabouraud Dextrose Agar with Chloramphenicol (SDA), Brain and Heart Infusion Agar (BHI), Chromagar and Blood Agar. All experiments were performed in triplicate and analyze... (Complete abstract click electronic access below) / Mestre

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