Polymer- and Hybrid-Based Biomaterials for Interstitial, Connective, Vascular, Nerve, Visceral and Musculoskeletal Tissue Engineering

In this review, materials based on polymers and hybrids possessing both organic and inorganic contents for repairing or facilitating cell growth in tissue engineering are discussed. Pure polymer based biomaterials are predominantly used to target soft tissues. Stipulated by possibilities of tuning the composition and concentration of their inorganic content, hybrid materials allow to mimic properties of various types of harder tissues. That leads to the concept of “one-matches-all” referring to materials possessing the same polymeric base, but different inorganic content to enable tissue growth and repair, proliferation of cells, and the formation of the ECM (extra cellular matrix). Furthermore, adding drug delivery carriers to coatings and scaffolds designed with such materials brings additional functionality by encapsulating active molecules, antibacterial agents, and growth factors. We discuss here materials and methods of their assembly from a general perspective together with their applications in various tissue engineering sub-areas: interstitial, connective, vascular, nervous, visceral and musculoskeletal tissues. The overall aims of this review are two-fold: (a) to describe the needs and opportunities in the field of bio-medicine, which should be useful for material scientists, and (b) to present capabilities and resources available in the area of materials, which should be of interest for biologists and medical doctors.</jats:p

Colloids-at-surfaces : physicochemical approaches for facilitating cell adhesion on hybrid hydrogels

Implementation of an effective focal cell adhesion represents a significant challenge because it requires to develop appropriate materials and processes together with assuring that cells would interact with it effectively. Various coatings are under development in the area of biomaterials including hydrogels and polymeric surfaces. Here, we analyse modification of the coatings by colloidal nano- and micro-particles, which effectively modify the surface of soft hydrogel materials, enhance and allow for adjustment of mechanical properties, and enable molecule release capabilities. A classification of such hybrid coatings is presented, where natural and synthetic polymeric coatings are overviewed. These organic coatings are modified by inorganic micro- and nano- particles. Various approaches to the design of such hybrid coatings are overviewed, while additional functionalities such as release of encapsulated biomolecules and enhancement of mechanical properties are highlighted. The developments in this area target effective cell growth, which is shown to be enhanced by the addition of colloidal particles

Identification and analysis of key parameters for the ossification on particle functionalized composites hydrogel materials

Developing materials for tissue engineering and studying the mechanisms of cell adhesion is a complex and multifactor process that needs analysis using physical chemistry and biology. The major challenge is the labor-intensive data mining as well as requirements of the number of advanced techniques. For example, hydrogel-based biomaterials with cell-binding sites, tunable mechanical properties and complex architectures have emerged as a powerful tool to control cell adhesion and proliferation for tissue engineering. Composite hydrogels could be used for bone tissue regeneration, but they exhibit poor ossification properties. In current work, we have designed new osteoinductive gellan gum hydrogels by a thermal annealing approach and consequently functionalized them with Ca/Mg carbonates submicron particles. Determination of key parameters, which influence a successful hydroxyapatite generation, were done via the principal component analysis of 18 parameters (Young’s modulus of the hydrogel and particles, particles size and mass) and cell behaviour at various time points (like viability, numbers of the cells, rate of alkaline phosphatase production and cells area) obtained by characterizing such composite hydrogel. It is determined that the particles size and concentration of calcium ions have a dominant effect on the hydroxyapatite formation, because of providing local areas with a high Young’s modulus in a hydrogel – a desirable property for cell adhesion. The presented here detailed analysis allows identifying hydrogels for cell growth applications, while on the other hand, material properties can be predicted, and their overall number can be minimized leading to efficient optimization of bone reconstruction and other cell growth applications

Magnetic and silver nanoparticle functionalized calcium carbonate particles : dual functionality of versatile, movable delivery carriers which can surface-enhance Raman signals

Multifunctional probes play an increasing role even beyond applications in biomedicine. Multifunctionality introduced by the dual types of complementary probes is always attractive because, in this case, functionalized objects inherit the function of both materials. Porous calcium carbonate microparticles are becoming popular carriers of biomolecules and biosensors, as well as imaging enhancers. We demonstrate here a dual function of these carriers by incorporating both magnetic and silver nanoparticles. Magnetic nanoparticles enable movements and displacements by a magnetic field, while silver nanoparticles provide surface-enhanced Raman signal amplification necessary for the detection of biomolecules. Application of such dual-functional carriers is foreseen beyond the applications of biomedicine and theranostics

Carbon nanotubes transform soft gellan gum hydrogels into hybrid organic–inorganic coatings with excellent cell growth capability

Carbone nanotubes (CNTs) possess distinct properties, for example, hardness, which is very complementary to biologically relevant soft polymeric and protein materials. Combining CNTs with bio-interfaces leads to obtaining new materials with advanced properties. In this work, we have designed novel organic-inorganic hybrid coatings by combining CNTs with gellan gum (GG) hydrogels. The surface topography of the samples is investigated using scanning electron microscopy and atomic force microscopy. Mechanical properties of synthesized hybrid materials are both assessed at the macro-scale and mapped at the nanoscale. A clear correlation between the CNT concentration and the hardness of the coatings is revealed. Cell culture studies show that effective cell growth is achieved at the CNT concentration of 15 mg/mL. The presented materials can open new perspectives for hybrid bio-interfaces and can serve as a platform for advanced cell culture

Fabrication and impact of fouling-reducing temperature-responsive POEGMA coatings with embedded CaCO3 nanoparticles on different cell lines

In the present work, we have successfully prepared and characterized novel nanocomposite material exhibiting temperature-dependent surface wettability changes, based on grafted brush coatings of non-fouling poly(di(ethylene glycol)methyl ether methacrylate) (POEGMA) with the embedded CaCO3 nanoparticles. Grafted polymer brushes attached to the glass surface were prepared in a three-step process using atom transfer radical polymerization (ATRP). Subsequently, uniform CaCO3 nanoparticles (NPs) embedded in POEGMA-grafted brush coatings were synthesized using biomineralized precipitation from solutions of CaCl2 and Na2CO3. An impact of the low concentration of the embedded CaCO3 NPs on cell adhesion and growth depends strongly on the type of studied cell line: keratinocytes (HaCaT), melanoma (WM35) and osteoblastic (MC3T3-e1). Based on the temperature-responsive properties of grafted brush coatings and CaCO3 NPs acting as biologically active substrate, we hope that our research will lead to a new platform for tissue engineering with modified growth of the cells due to the release of biologically active substances from CaCO3 NPs and the ability to detach the cells in a controlled manner using temperature-induced changes of the brush

Improving cell adhesion by designing hydrogel-based coatings for tissue engineering

Polymeric hydrogels are an important class of functional soft materials composed of a large variety of neutral or charged hydrophilic macromolecules cross-linked chemically or physically in an aqueous environment. The water-rich nature of hydrogels resembles biological tissues opening up opportunities for their application in biomedical areas, such as tissue engineering. However, the mere presence of a matrix for cell growth is often not sufficient for a good cell adhesion and proliferation; this requires other components, which provide additional functionalities, for example: improve cell adhesion, stimulate ossification process, provide antibacterial protection, etc (polymers, nano- and micro- particles, biological molecules, such as growth factors, enzymes, DNA or RNA). That stimulates development of hydrogel-based hybrid materials incorporating both organic and inorganic components. Hydrogel-based hybrid materials are emerging as a very potent and promising class of materials due to their diverse properties, which are proved to be a viable tool for tissue engineering applications allowing to improve cell adhesion and formation of the extracellular matrix (ECM) and tissue regeneration. Novel processes of hydrogel matrix synthesis, incorporation of inorganic particles and bioactive molecules as well as assembly of new particle-like surfaces are developed in this work to improve and facilitate cell adhesion and proliferation. Specifically: (1) hydrogel modification via thermal annealing process is conducted, which changes pore sizes, mechanical properties, fibril clustering, and the morphology of hydrogels from mesh to fibers; (2) design of composite Gellan Gum (GG) is pursued by functionalizing it with carbon nanotubes, which result in a significant improvement of cell adhesion; (3) functionalization of hydrogels with calcium and magnesium carbonate minerals is performed for hydroxyapatite (HA) produced by cells on composite GG hydrogels; (4) investigation of cell adhesion on CaCO3 microparticles on the surface of composite alginate hydrogels with distinct local nano- and macro- scale mechanical properties is carried out; (5) novel hybrid materials are designed by shrinking inorganic/organic nanostructured alginate/vaterite spheroids modified with alkaline phosphatase for acceleration of ossification. Analysis of described above samples and phenomena is based on architectural, mechanical, and chemical properties, where the interaction of cells with the samples and their further behavior on the surface remains an important factor. 20 To prove that cells proliferate and perform ECM biosynthesis on synthesized biomaterials, osteoblast cells are selected, which form an ECM consisting of collagen and HA. Therefore, we study a possibility to enhance the cell ossification by functionalizing the hydrogel matrix by carbonate-based particles with various size, shape, composition, and concertation. As a result, a possibility to enhance the ECM formation is investigated by designing tissue engineering structures, which are also applied to study cell adhesion on the colloidal particles. Our results emphasize the added value of hydrogel-based hybrid materials and approaches, particularly involving functionalization by microparticles and bioactive molecules. Such new materials are envisioned to find applications in tissue engineering, biomedicine, and biology

3D Cell Spheroids as a Tool for Evaluating the Effectiveness of Carbon Nanotubes as a Drug Delivery and Photothermal Therapy Agents

Cell spheroids (CSs) are three-dimensional models in vitro that have a microenvironment similar to tissues. Such three-dimensional cellular structures are of great interest in the field of nano biomedical research, as they can simulate information about the characteristics of nanoparticles (NPs) by avoiding the use of laboratory animals. Due to the development of areas such as bioethics and tissue engineering, it is expected that the use of such 3D cell structures will become an even more valuable tool in the hands of researchers. We present an overview of carbon nanotubes (CNTs) research on CSs in order to determine the mechanism of their incorporation into CSs, drug delivery, and photothermal therapy. We will look at such areas as the application of CNTs for medical purposes, the advantages of spheroids over classical 2D cell culture, the ways in which CNTs pass into the intercellular space, and the ways in which they are absorbed by cells in a three-dimensional environment, the use of the spheroid model for such studies as drug delivery and photothermal therapy. Thus, CSs are suitable models for obtaining additional information on the required properties of CNTs in their application in nanobiomedicine

Calcium carbonate particles : synthesis, temperature and time influence on the size, shape, phase, and their impact on cell hydroxyapatite formation

To develop materials for drug delivery and tissue engineering and to study their efficiency with respect to ossification, it is necessary to apply physicochemical and biological analyses. The major challenge is labor-intensive data mining during synthesis and the reproducibility of the obtained data. In this work, we investigated the influence of time and temperature on the reaction yield, the reaction rate, and the size, shape, and phase of the obtained product in the completely controllable synthesis of calcium carbonate. We show that calcium carbonate particles can be synthesized in large quantities, i.e., in gram quantities, which is a substantial advantage over previously reported synthesis methods. We demonstrated that the presence of vaterite particles can dramatically stimulate hydroxyapatite (HA) production by providing the continued release of the main HA component - calcium ions - depending on the following particle parameters: size, shape, and phase. To understand the key parameters influencing the efficiency of HA production by cells, we created a predictive model by means of principal component analysis. We found that smaller particles in the vaterite state are best suited for HA growth (HA growth was 8 times greater than that in the control). We also found that the reported dependence of cell adhesion on colloidal particles can be extended to other types of particles that contain calcium ions

Key Points in Remote-Controlled Drug Delivery: From the Carrier Design to Clinical Trials

The increased research activity aiming at improved delivery of pharmaceutical molecules indicates the expansion of the field. An efficient therapeutic delivery approach is based on the optimal choice of drug-carrying vehicle, successful targeting, and payload release enabling the site-specific accumulation of the therapeutic molecules. However, designing the formulation endowed with the targeting properties in vitro does not guarantee its selective delivery in vivo. The various biological barriers that the carrier encounters upon intravascular administration should be adequately addressed in its overall design to reduce the off-target effects and unwanted toxicity in vivo and thereby enhance the therapeutic efficacy of the payload. Here, we discuss the main parameters of remote-controlled drug delivery systems: (i) key principles of the carrier selection; (ii) the most significant physiological barriers and limitations associated with the drug delivery; (iii) major concepts for its targeting and cargo release stimulation by external stimuli in vivo. The clinical translation for drug delivery systems is also described along with the main challenges, key parameters, and examples of successfully translated drug delivery platforms. The essential steps on the way from drug delivery system design to clinical trials are summarized, arranged, and discussed