Regulation of the Ocular Cell/Tissue Response by Implantable Biomaterials and Drug Delivery Systems

Therapeutic advancements in the treatment of various ocular diseases is often linked to the development of efficient drug delivery systems (DDSs), which would allow a sustained release while maintaining therapeutic drug levels in the target tissues. In this way, ocular tissue/cell response can be properly modulated and designed in order to produce a therapeutic effect. An ideal ocular DDS should encapsulate and release the appropriate drug concentration to the target tissue (therapeutic but non-toxic level) while preserving drug functionality. Furthermore, a constant release is usually preferred, keeping the initial burst to a minimum. Different materials are used, modified, and combined in order to achieve a sustained drug release in both the anterior and posterior segments of the eye. After giving a picture of the different strategies adopted for ocular drug release, this review article provides an overview of the biomaterials that are used as drug carriers in the eye, including micro- and nanospheres, liposomes, hydrogels, and multi-material implants; the advantages and limitations of these DDSs are discussed in reference to the major ocular applications

Natural-origin materials for tissue engineering and regenerative medicine

Recent advances in tissue engineering and regenerative medicine have shown that combining biomaterials, cells, and bioactive molecules are important to promote the regeneration of damaged tissues or as therapeutic systems. Natural origin polymers have been used as matrices in such applications due to their biocompatibility and biodegradability. This article provides an up-to-date review on the most promising natural biopolymers, focused on polysaccharides and proteins, their properties and applications. Membranes, micro/nanoparticles, scaffolds, and hydrogels as biomimetic strategies for tissue engineering and processing are described, along with the use of bioactive molecules and growth factors to improve tissue regeneration potential. Finally, current biomedical applications are also presented.The authors would like to thank to the financial support from the Portuguese Foundation for Science and Technology (FCT) for the fellowship grants of Simone S Silva (SFRH/BPD/112140/2015), Emanuel M Fernandes (SFRH/BPD/96197/2013), Joana-Silva Correira (SFRH/BPD/100590/2014), Sandra Pina (SFRH/BPD/108763/2015), Silvia Vieira (SFRH/BD/102710/2014), “Fundo Social Europeu”- FSE and “ Programa Diferencial de Potencial Humano POPH”, and to the distinction attributed to J.M. Oliveira under the Investigator FCT program (IF/00423/2012). It is also greatly acknowledged the funds provided by FCT through the project EPIDisc (UTAP-EXPL/BBBECT/0050/2014), financed in the Framework of the “International Collaboratory for Emerging Technologies, CoLab”, UT Austin|Portugal Program.info:eu-repo/semantics/publishedVersio

ORBITAL FLOOR REGENERATION USING CYCLIC ACETAL HYDROGELS THROUGH ENHANCED OSTEOGENIC CELL SIGNALING OF MESENCHYMAL STEM CELLS

Orbital floor fractures are a serious consequence of craniofacial trauma and account for approximately 60-70% of all orbital fractures. Unfortunately, the body's natural response to orbital floor defects generally does not restore proper function and facial aesthetics which is complicated by the thin bone and adjacent sinuses. We propose using a tissue engineering strategy to regenerate orbital floor bone. To this end, a functional biomaterial was investigated to enhance orbital floor regeneration. First, a bone marrow stromal cell population was isolated and differentiation assessed via coculture with chondrocytes and osteogenic media supplements. A cyclic acetal biomaterial composed of the cyclic acetal monomer 5-ethyl-5-(hydroxymethyl)-β,β-dimethyl-1,3-dioxane-2-ethanol diacrylate (EHD) and poly(ethylene glycol) diacrylate (PEGDA) was then developed for cell encapsulation. The previously investigated bone marrow stromal cells were then used to determine the effects of the ammonium persulfate/N,N,N',N'-tetramethylethylenediamine initiator system used to crosslink the EH-PEG hydrogels on cell viability, metabolic activity, and osteogenic differentiation. Next, EH-PEG hydrogels were implanted into orbital floor defects with bone morphogenetic protein-2, where tissue response and surrounding bone growth was analyzed. To improve surrounding tissue interaction and cell infiltration, macroporous EH-PEG hydrogels were created using porogen-leaching. These hydrogels were characterized using optical coherence tomography for pore size, porosity, and cell viability. In addition, these macroporous hydrogels were created with varying architecture to analyze the effects on osteogenic signaling and differentiation. This work outlines the potential application of EH-PEG hydrogels for use in orbital floor repair

Functionalized Nanostructures with Application in Regenerative Medicine

In the last decade, both regenerative medicine and nanotechnology have been broadly developed leading important advances in biomedical research as well as in clinical practice. The manipulation on the molecular level and the use of several functionalized nanoscaled materials has application in various fields of regenerative medicine including tissue engineering, cell therapy, diagnosis and drug and gene delivery. The themes covered in this review include nanoparticle systems for tracking transplanted stem cells, self-assembling peptides, nanoparticles for gene delivery into stem cells and biomimetic scaffolds useful for 2D and 3D tissue cell cultures, transplantation and clinical application

Progenitor cells in auricular cartilage demonstrate promising cartilage regenerative potential in 3D hydrogel culture

The reconstruction of auricular deformities is a very challenging surgical procedure that could benefit from a tissue engineering approach. Nevertheless, a major obstacle is presented by the acquisition of sufficient amounts of autologous cells to create a cartilage construct the size of the human ear. Extensively expanded chondrocytes are unable to retain their phenotype, while bone marrow-derived mesenchymal stromal cells (MSC) show endochondral terminal differentiation by formation of a calcified matrix. The identification of tissue-specific progenitor cells in auricular cartilage, which can be expanded to high numbers without loss of cartilage phenotype, has great prospects for cartilage regeneration of larger constructs. This study investigates the largely unexplored potential of auricular progenitor cells for cartilage tissue engineering in 3D hydrogels

ENGINEERING CELLULAR MICROENVIRONMENT FOR CARTILAGE REGENERATION

Articular cartilage defects, resulting from trauma or pathological change, affect a large population worldwide from adolescents to adults. The limited self-renewal ability of cartilage due to lack of blood vessels and cellular crosstalk makes it one of the most difficult tissues to regenerate. Common treatments to prevent the progression of critical cartilage defects involve surgical intervention such as microfracture and autologous chondrocyte implantation. Besides the time and cost involved in these clinical treatments, the quality of the regenerated tissue is not comparable to native tissue in regard to biological function; the cartilage synthesized at the defect region becomes fibrous and prone to failure over time, possibly due to the absence of required cellular microenvironment. To overcome the difficulties in cell expansion associated with chondrocytes, human mesenchymal stem cell (hMSC) has been explored as an alternative cell source for its abundance and ability to differentiate into chondrocytes. The work presented here is aimed at recapitulating the complex microenvironment of cartilage tissue by guiding stem cell alignment and differentiation on a 3D patterned scaffold to improve the repair outcome. The first aim of this work examined cellular responses to the addition of mechanical preconditioning in an environment which incorporated signaling molecules and supporting matrices. Our developed compression-perfusion bioreactor provided a solution to enhance chondrogenic differentiation of hMSCs by providing mechanical stimulation that recapitulates the native environment. The second aim of the thesis extended the development of cellular environment to the use of 3D printed scaffold with controlled micro-patterns. During extrusion 3D printing, sheered polymer generated an organized micro-environment of aligned polymer molecules that had an impact on cell alignment and differentiation. The scaffold was then functionalized with aggrecan and applied to an in vivo model combined the standard approach of microfracture to evaluate the regenerative potential. The results demonstrated improved quality of the newly formed cartilage tissue. In this dissertation, we have investigated the cellular microenvironment that provides both mechanical and biological cues for cartilage regeneration. The acellular patterned scaffold that provides controlled cell behavior in combination with current surgical procedures will provide a cost-effective way to restore better cartilage function