Artificial Extracellular Matrices Research Articles

Heterocellular Adhesion in Cancer Invasion and Metastasis: Interactions between Cancer Cells and Cancer-Associated Fibroblasts.

Cancer invasion is a requisite for the most malignant progression of cancer, that is, metastasis. The mechanisms of cancer invasion were originally studied using in vitro cell culture systems, in which cancer cells were cultured using artificial extracellular matrices (ECMs). However, conventional culture systems do not precisely recapitulate in vivo cancer invasion because the phenotypes of cancer cells in tumor tissues are strongly affected by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the TME and accelerate cancer progression through invasion, metastasis, therapy resistance, and immune suppression. Thus, the reciprocal interactions between CAFs and cancer cells have been extensively studied, leading to the identification of factors that mediate cellular interactions, such as growth factors, cytokines, and extracellular vesicles. In addition, the importance of direct heterocellular adhesion between cancer cells and CAFs in cancer progression has recently been elucidated. In particular, CAFs are directly associated with cancer cells, allowing them to invade the ECM and metastasize to distant organs. In this review, we summarize the recent progress in understanding the molecular and cellular mechanisms of the direct heterocellular interaction in CAF-led cancer invasion and metastasis, with an emphasis on gastric cancer.

Nanocellulose-based hydrogels as versatile materials with interesting functional properties for tissue engineering applications.

Tissue engineering has emerged as a remarkable field aiming to restore or replace damaged tissues through the use of biomimetic constructs. Among the diverse materials investigated for this purpose, nanocellulose-based hydrogels have garnered attention due to their intriguing biocompatibility, tunable mechanical properties, and sustainability. Over the past few years, numerous research works have been published focusing on the successful use of nanocellulose-based hydrogels as artificial extracellular matrices for regenerating various types of tissues. The review emphasizes the importance of tissue engineering, highlighting hydrogels as biomimetic scaffolds, and specifically focuses on the role of nanocellulose in composites that mimic the structures, properties, and functions of the native extracellular matrix for regenerating damaged tissues. It also summarizes the types of nanocellulose, as well as their structural, mechanical, and biological properties, and their contributions to enhancing the properties and characteristics of functional hydrogels for tissue engineering of skin, bone, cartilage, heart, nerves and blood vessels. Additionally, recent advancements in the application of nanocellulose-based hydrogels for tissue engineering have been evaluated and documented. The review also addresses the challenges encountered in their fabrication while exploring the potential future prospects of these hydrogel matrices for biomedical applications.

A self-assembling peptide nanofiber hydrogel for biomaterials with rapid stimulation response to naturally positively charged group substances

Peptides as unique supramolecular nanofibrous materials are favored choices to fabricate hydrogel for artificial extracellular matrices. Herein, we devised an amphiphilic polypeptide that could be motivated by multiple substances with positively charged group at physiological temperature and pH to assemble supramolecular nanofiber hydrogels since the electrostatic repulsion between monomers was attenuated. The hydrogelation phenomenon and spectroscopy were compatible with molecular dynamics simulations (MDs) results for revealing the assembly mechanism of this peptide, confirming that the behavior of assembling and the typical secondary structure of the assemblies was β-sheet. The impact of peptide concentration on the mechanical properties of hydrogels were described using rheology. We found that the peptide formed elastic gels from 0.3 wt% onwards in practical use and that these recovered by themselves after shear thinning that indicated they were injectable hydrogels. The successful establishment of cell spheres with high cell viability during 15 days culture in 3D space demonstrated the nanofiber hydrogels had potential in cell model construction and microtissue culture. Overall, the superior biologically friendly gel-forming conditions and excellent biological properties of this supramolecular assembly peptide material have invigorated the progress of biomedical fields such as tissue regeneration based on in vitro 3D culture.

Long-term in vitro culture of 3D brain tissue model based on chitosan thermogel

Methods for studying brain function and disease heavily rely on in vivo animal models, ex-vivo tissue slices, and 2D cell culture platforms. These methods all have limitations that significantly impact the clinical translatability of results. Consequently, models able to better recapitulate some aspects of in vivo human brain are needed as additional preclinical tools. In this context, 3D hydrogel-based in vitro models of the brain are considered promising tools. To create a 3D brain-on-a-chip model, a hydrogel capable of sustaining neuronal maturation over extended culture periods is required. Among biopolymeric hydrogels, chitosan-β-glycerophosphate (CHITO-β-GP) thermogels have demonstrated their versatility and applicability in the biomedical field over the years. In this study, we investigated the ability of this thermogel to encapsulate neuronal cells and support the functional maturation of a 3D neuronal network in long-term cultures. To the best of our knowledge, we demonstrated for the first time that CHITO-β-GP thermogel possesses optimal characteristics for promoting neuronal growth and the development of an electrophysiologically functional neuronal network derived from both primary rat neurons and neurons differentiated from human induced pluripotent stem cells (h-iPSCs) co-cultured with astrocytes. Specifically, two different formulations were firstly characterized by rheological, mechanical and injectability tests. Primary nervous cells and neurons differentiated from h-iPSCs were embedded into the two thermogel formulations. The 3D cultures were then deeply characterized by immunocytochemistry, confocal microscopy, and electrophysiological recordings, employing both 2D and 3D micro-electrode arrays. The thermogels supported the long-term culture of neuronal networks for up to 100 d. In conclusion, CHITO-β-GP thermogels exhibit excellent mechanical properties, stability over time under culture conditions, and bioactivity toward nervous cells. Therefore, they are excellent candidates as artificial extracellular matrices in brain-on-a-chip models, with applications in neurodegenerative disease modeling, drug screening, and neurotoxicity evaluation.

One-Pot Approach to Synthesize Tough and Cell Adhesive Double-Network Hydrogels Consisting of Fully Synthetic Materials of Self-Assembling Peptide and Poly(ethylene glycol).

Hydrogels with a double network (DN) structure are compelling biomaterials, holding potential for use as artificial extracellular matrices. Generally, the DN approach imparts hydrogels with high mechanical strength and cell-adhesive properties. However, achieving this often demands a complex multistep process involving potentially hazardous free-radical polymerization, which can result in toxicity. This limits their broad biological applications. In this work, we introduce a straightforward yet biocompatible method to fabricate tough and cell-adhesive DN hydrogels using entirely synthetic materials: the self-assembling peptide (RADA16) and poly(ethylene glycol) (PEG). An in situ mixing of these components leads to the sequential formation of DN hydrogels─first through the self-assembly of the RADA16 peptide and then via chemical cross-linking between PEG molecules. Hydrogels produced this way exhibited up to a 10-fold increase in fracture energy, and cells seeded on their surfaces showcased good attachment. Our design underscores the efficacy of the DN approach and the promising applications of peptides in tissue engineering.

Tannic Acid-Induced Gelation of Aqueous Suspensions of Cellulose Nanocrystals.

Nanocellulose hydrogels are a crucial category of soft biomaterials with versatile applications in tissue engineering, artificial extracellular matrices, and drug-delivery systems. In the present work, a simple and novel method, involving the self-assembly of cellulose nanocrystals (CNCs) induced by tannic acid (TA), was developed to construct a stable hydrogel (SH-CNC/TA) with oriented porous network structures. The gelation process is driven by the H-bonding interaction between the hydroxyl groups of CNCs and the catechol groups of TA, as substantiated by the atoms in molecules topology analysis and FTIR spectra. Interestingly, the assembled hydrogels exhibited a tunable hierarchical porous structure and mechanical moduli by varying the mass ratio of CNCs to TA. Furthermore, these hydrogels also demonstrate rapid self-healing ability due to the dynamic nature of the H-bond. Additionally, the structural stability of the SH-CNC/TA hydrogel could be further enhanced and adjusted by introducing coordination bonding between metal cations and TA. This H-bonding driven self-assembly method may promote the development of smart cellulose hydrogels with unique microstructures and properties for biomedical and other applications.

Versatile click alginate hydrogels with protease-sensitive domains as cell responsive/instructive 3D microenvironments

Alginate (ALG) is a widely used biomaterial to create artificial extracellular matrices (ECM) for tissue engineering. Since it does not degrade in the human body, imparting proteolytic sensitivity to ALG hydrogels leverages their properties as ECM-mimics. Herein, we explored the strain-promoted azide-alkyne cycloaddition (SPAAC) as a biocompatible and bio-orthogonal click-chemistry to graft cyclooctyne-modified alginate (ALG-K) with bi-azide-functionalized PVGLIG peptides. These are sensitive to matrix metalloproteinase (MMP) and may act as crosslinkers. The ALG-K-PVGLIG conjugates (50, 125, and 250 μM PVGLIG) were characterized for peptide incorporation, crosslinking ability (double-end grafting), and enzymatic liability. For producing cell-permissive multifunctional 3D matrices for dermal fibroblast culture, oxidized ALG-K was grafted with PVGLIG and with RGD peptides for cell-adhesion. SPAAC reactions were performed immediately before cell-laden hydrogel formation by secondary ionic-crosslinking, considerably reducing the steps and time of preparation. Hydrogels with intermediate PVGLIG concentration (125 μM) presented slightly higher stiffness while promoting extensive cell spreading and higher degree of cell-cell interconnections, likely favored by cell-driven proteolytic remodeling of the network. The hydrogel-embedded cells were able to produce their own pericellular ECM, expressed MMP-2 and 14, and secreted PVGLIG-degrading enzymes. By recapitulating key ECM-like features, these hydrogels provide biologically relevant 3D matrices for soft tissue regeneration.

Gelatin/Na2Ti3O7 Nanocomposite Scaffolds: Mechanical Properties and Characterization for Tissue Engineering Applications.

Materials and manufacturing technologies are necessary for tissue engineering and developing temporary artificial extracellular matrices. In this study, scaffolds were fabricated from freshly synthesized titanate (Na2Ti3O7) and its precursor titanium dioxide and their properties were investigated. The scaffolds with improved properties were then mixed with gelatin to form a scaffold material using the freeze-drying technique. To determine the optimal composition for the compression test of the nanocomposite scaffold, a mixture design with three factors of gelatin, titanate, and deionized water was used. Then, the scaffold microstructures were examined by scanning electron microscopy (SEM) to determine the porosity of the nanocomposite scaffolds. The scaffolds were fabricated as a nanocomposite and determined their compressive modulus values. The results showed that the porosity of the gelatin/Na2Ti3O7 nanocomposite scaffolds ranged from 67% to 85%. When the mixing ratio was 100:0, the degree of swelling was 22.98%. The highest swelling ratio of 85.43% was obtained when the freeze-drying technique was applied to the mixture of gelatin and Na2Ti3O7 with a mixing ratio of 80:20. The specimens formed (gelatin:titanate = 80:20) exhibited a compressive modulus of 30.57 kPa. The sample with a composition of 15.10% gelatin, 2% Na2Ti3O7, and 82.9% DI water, processed by the mixture design technique, showed the highest yield of 30.57 kPa in the compression test.

Nanocomposite Hydrogels as Functional Extracellular Matrices

Over recent years, nano-engineered materials have become an important component of artificial extracellular matrices. On one hand, these materials enable static enhancement of the bulk properties of cell scaffolds, for instance, they can alter mechanical properties or electrical conductivity, in order to better mimic the in vivo cell environment. Yet, many nanomaterials also exhibit dynamic, remotely tunable optical, electrical, magnetic, or acoustic properties, and therefore, can be used to non-invasively deliver localized, dynamic stimuli to cells cultured in artificial ECMs in three dimensions. Vice versa, the same, functional nanomaterials, can also report changing environmental conditions-whether or not, as a result of a dynamically applied stimulus-and as such provide means for wireless, long-term monitoring of the cell status inside the culture. In this review article, we present an overview of the technological advances regarding the incorporation of functional nanomaterials in artificial extracellular matrices, highlighting both passive and dynamically tunable nano-engineered components.

Artificial Extracellular Matrix Composed of Heparin-Mimicking Polymers for Efficient Anticoagulation and Promotion of Endothelial Cell Proliferation.

Heparin-mimicking polymers have emerged as an alternative to heparin to construct effective and safe anticoagulant surfaces. However, the present heparin-mimicking polymers are usually limited to the combinations of glucose and sulfonic acid units, and the structure origin of their anticoagulant properties remains vague. Inspired by the structure of natural heparin, we synthesized a series of novel heparin-mimicking polymers (named GSAs) composed of three units, glucose, sulfonic acid, and carboxylic acid. Then, we constructed artificial extracellular matrices composed of GSAs and two typical cationic polymers, polyethyleneimine and chitosan, to investigate the anticoagulation and endothelialization of GSAs. By changing the ratio of the three units, their functions in the matrices were studied systematically. We found that an increase in the sulfonic acid content enhanced surface anticoagulant activity, an increase in glucose and sulfonic acid content promoted the proliferation of human umbilical vein vascular endothelial cells, and an increase in the carboxylic acid content inhibited the adherence of human umbilical vein vascular smooth muscle cells. This work uncovers the important role of the GSAs structure to the anticoagulation properties, which sheds new light on the design and preparation of heparin-mimicking polymers for practical engineering applications.

Electrospun Biomimetic Nanofibrous Scaffolds: A Promising Prospect for Bone Tissue Engineering and Regenerative Medicine.

Skeletal-related disorders such as arthritis, bone cancer, osteosarcoma, and osteoarthritis are among the most common reasons for mortality in humans at present. Nanostructured scaffolds have been discovered to be more efficient for bone regeneration than macro/micro-sized scaffolds because they sufficiently permit cell adhesion, proliferation, and chemical transformation. Nanofibrous scaffolds mimicking artificial extracellular matrices provide a natural environment for tissue regeneration owing to their large surface area, high porosity, and appreciable drug loading capacity. Here, we review recent progress and possible future prospective electrospun nanofibrous scaffolds for bone tissue engineering. Electrospun nanofibrous scaffolds have demonstrated promising potential in bone tissue regeneration using a variety of nanomaterials. This review focused on the crucial role of electrospun nanofibrous scaffolds in biological applications, including drug/growth factor delivery to bone tissue regeneration. Natural and synthetic polymeric nanofibrous scaffolds are extensively inspected to regenerate bone tissue. We focused mainly on the significant impact of nanofibrous composite scaffolds on cell adhesion and function, and different composites of organic/inorganic nanoparticles with nanofiber scaffolds. This analysis provides an overview of nanofibrous scaffold-based bone regeneration strategies; however, the same concepts can be applied to other organ and tissue regeneration tactics.

Evaluation of In Vitro Tools to Predict the In Vivo Absorption of Biopharmaceuticals Following Subcutaneous Administration

PurposeFor injectable biopharmaceuticals, the subcutaneous route of administration is increasingly preferred over intravenous administration. However, one of the challenges in the development of subcutaneously administered biopharmaceuticals is a reduced bioavailability, which is difficult to predict. Since animal models do not reliably reflect bioavailability in patients, in vitro models could help to develop drug candidates. The purpose of this study was to evaluate a versatile set of in vitro tools for their suitability to predict bioavailability of biopharmaceuticals after subcutaneous administration. MethodsWe examined seven commercially available biopharmaceuticals using three instruments, i.e., the Subcutaneous Injection Site Simulator (Scissor), the Osmomat 050, and a dialysis system using three artificial extracellular matrices, two dissolution apparatuses, i.e., the USP4 and the USP7, and two evaluation tools, i.e., the affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) and the Developability Index (DI). Results were evaluated for their usefulness to predict the bioavailability and other pharmacokinetic parameters in humans using the Pearson correlation. ResultsNone of the tested instruments and methods could reliably approximate bioavailability. Only pressure values derived with the Osmomat 050 instrument correlated with Cmax with a Pearson correlation coefficient greater than 0.8. ConclusionNo single in vitro method confidently predicted the bioavailability in humans. We only found a correlation to maximum plasma concentration values for one of the tested approaches. However, a more focused evaluation would be necessary to confirm our findings and test combinations of orthogonal methods that may improve the confidence of such a prediction

Genipin-Crosslinked, Proteosaccharide Scaffolds for Potential Neural Tissue Engineering Applications.

Traumatic brain injuries (TBIs) are still a challenge for the field of modern medicine. Many treatment options such as autologous grafts and stem cells show limited promise for the treatment and the reversibility of damage caused by TBIs. Injury beyond the critical size necessitates the implementation of scaffolds that function as surrogate extracellular matrices. Two scaffolds were synthesised utilising polysaccharides, chitosan and hyaluronic acid in conjunction with gelatin. Both scaffolds were chemically crosslinked using a naturally derived crosslinker, Genipin. The polysaccharides increased the mechanical strength of each scaffold, while gelatin provided the bioactive sequence, which promoted cellular interactions. The effect of crosslinking was investigated, and the crosslinked hydrogels showed higher thermal decomposition temperatures, increased resistance to degradation, and pore sizes ranging from 72.789 ± 16.85 µm for the full interpenetrating polymer networks (IPNs) and 84.289 ± 7.658 μm for the semi-IPN. The scaffolds were loaded with Dexamethasone-21-phosphate to investigate their efficacy as a drug delivery vehicle, and the full IPN showed a 100% release in 10 days, while the semi-IPN showed a burst release in 6 h. Both scaffolds stimulated the proliferation of rat pheochromocytoma (PC12) and human glioblastoma multiforme (A172) cell cultures and also provided signals for A172 cell migration. Both scaffolds can be used as potential drug delivery vehicles and as artificial extracellular matrices for potential neural regeneration.

Biosensors to Monitor Cell Activity in 3D Hydrogel-Based Tissue Models.

Three-dimensional (3D) culture models have gained relevant interest in tissue engineering and drug discovery owing to their suitability to reproduce in vitro some key aspects of human tissues and to provide predictive information for in vivo tests. In this context, the use of hydrogels as artificial extracellular matrices is of paramount relevance, since they allow closer recapitulation of (patho)physiological features of human tissues. However, most of the analyses aimed at characterizing these models are based on time-consuming and endpoint assays, which can provide only static and limited data on cellular behavior. On the other hand, biosensing systems could be adopted to measure on-line cellular activity, as currently performed in bi-dimensional, i.e., monolayer, cell culture systems; however, their translation and integration within 3D hydrogel-based systems is not straight forward, due to the geometry and materials properties of these advanced cell culturing approaches. Therefore, researchers have adopted different strategies, through the development of biochemical, electrochemical and optical sensors, but challenges still remain in employing these devices. In this review, after examining recent advances in adapting existing biosensors from traditional cell monolayers to polymeric 3D cells cultures, we will focus on novel designs and outcomes of a range of biosensors specifically developed to provide real-time analysis of hydrogel-based cultures.

Combinatorial Approach of Binary Colloidal Crystals and CRISPR Activation to Improve Induced Pluripotent Stem Cell Differentiation into Neurons.

Conventional methods of neuronal differentiation in human induced pluripotent stem cells (iPSCs) are tedious and complicated, involving multistage protocols with complex cocktails of growth factors and small molecules. Artificial extracellular matrices with a defined surface topography and chemistry represent a promising venue to improve neuronal differentiation in vitro. In the present study, we test the impact of a type of colloidal self-assembled patterns (cSAPs) called binary colloidal crystals (BCCs) on neuronal differentiation. We developed a CRISPR activation (CRISPRa) iPSC platform that constitutively expresses the dCas9-VPR system, which allows robust activation of the proneural transcription factor NEUROD1 to rapidly induce neuronal differentiation within 7 days. We show that the combinatorial use of BCCs can further improve this neuronal differentiation system. In particular, our results indicate that fine tuning of silica (Si) and polystyrene (PS) particle size is critical to generate specific topographies to improve neuronal differentiation and branching. BCCs with 5 μm silica and 100 nm carboxylated PS (PSC) have the most prominent effect on increasing neurite outgrowth and more complex ramification, while BCCs with 2 μm Si and 65 nm PSC particles are better at promoting neuronal enrichment. These results indicate that biophysical cues can support rapid differentiation and improve neuronal maturation. In summary, our combinatorial approach of CRISPRa and BCCs provides a robust and rapid pipeline for the in vitro production of human neurons. Specific BCCs can be adapted to the late stages of neuronal differentiation protocols to improve neuronal maturation, which has important implications in tissue engineering, in vitro biological studies, and disease modeling.

Impact of Graphene Derivatives as Artificial Extracellular Matrices on Mesenchymal Stem Cells.

Thanks to stem cells’ capability to differentiate into multiple cell types, damaged human tissues and organs can be rapidly well-repaired. Therefore, their applicability in the emerging field of regenerative medicine can be further expanded, serving as a promising multifunctional tool for tissue engineering, treatments for various diseases, and other biomedical applications as well. However, the differentiation and survival of the stem cells into specific lineages is crucial to be exclusively controlled. In this frame, growth factors and chemical agents are utilized to stimulate and adjust proliferation and differentiation of the stem cells, although challenges related with degradation, side effects, and high cost should be overcome. Owing to their unique physicochemical and biological properties, graphene-based nanomaterials have been widely used as scaffolds to manipulate stem cell growth and differentiation potential. Herein, we provide the most recent research progress in mesenchymal stem cells (MSCs) growth, differentiation and function utilizing graphene derivatives as extracellular scaffolds. The interaction of graphene derivatives in human and rat MSCs has been also evaluated. Graphene-based nanomaterials are biocompatible, exhibiting a great potential applicability in stem-cell-mediated regenerative medicine as they may promote the behaviour control of the stem cells. Finally, the challenges, prospects and future trends in the field are discussed.

Artificial Extracellular Matrices Containing Bioactive Glass Nanoparticles Promote Osteogenic Differentiation in Human Mesenchymal Stem Cells.

The present study analyzes the capacity of collagen (coll)/sulfated glycosaminoglycan (sGAG)-based surface coatings containing bioactive glass nanoparticles (BGN) in promoting the osteogenic differentiation of human mesenchymal stroma cells (hMSC). Physicochemical characteristics of these coatings and their effects on proliferation and osteogenic differentiation of hMSC were investigated. BGN were stably incorporated into the artificial extracellular matrices (aECM). Oscillatory rheology showed predominantly elastic, gel-like properties of the coatings. The complex viscosity increased depending on the GAG component and was further elevated by adding BGN. BGN-containing aECM showed a release of silicon ions as well as an uptake of calcium ions. hMSC were able to proliferate on coll and coll/sGAG coatings, while cellular growth was delayed on aECM containing BGN. However, a stimulating effect of BGN on ALP activity and calcium deposition was shown. Furthermore, a synergistic effect of sGAG and BGN was found for some donors. Our findings demonstrated the promising potential of aECM and BGN combinations in promoting bone regeneration. Still, future work is required to further optimize the BGN/aECM combination for increasing its combined osteogenic effect.

Design, preparation and in vitro characterization of biomimetic and bioactive chitosan/polyethylene oxide based nanofibers as wound dressings

Chitosan-based nanofibers (CS-NFs) are excellent artificial extracellular matrices (ECMs) due to the resemblance of CS with the glycosaminoglycans of the natural ECMs. Despite this excellent feature, the poor electrospinnability and mechanical properties of CS are responsible for important limitations in respect to its biomedical applications. To improve the CS's physico-chemical properties, new bioactive and biomimetic CS-NFs were formulated with polyethylene oxide (PEO), having incorporated different active components (ACs) with important beneficial effects for healing. Manuka honey (trophic and antimicrobial effects), propolis (antimicrobial effects), Calendula officinalis infusion (antioxidant effect, reepithelialization stimulating agent), insulin (trophic effect), and L-arginine (angiogenic effect) were selected as ACs. SEM morphology analysis revealed well-alignment, unidirectional arrays, with small diameters, no beads, and smooth surfaces for developed CS_PEO-ACs NFs. The developed NFs showed good biodegradability (NFs mats lost up to 60% of their initial weight in PBS), increased hemocompatibility (hemolytic index less than 4%), and a reduced cytotoxicity degree (cell viability degree more than 90%). In addition, significant antioxidant and antimicrobial effects were noted for the developed NFs which make them suitable for chronic wounds, due to the role of oxidative stress and infection risk in delaying normal wound healing. The most suitable for wound healing applications seems to be CS_PEO@P_C which showed an improved hemolysis index (2.92 ± 0.16%), is non-toxic (cell viability degree more than 97%), and has also significant radical scavenging effect (DPPH inhibition more than 65%). In addition, CS_PEO@P_C presents increased antimicrobial effects, more noticeably for Staphylococcus aureus strain, which is a key feature in preventing wound infection and delaying the healing process. It can be concluded that the developed CS/PEO-ACs NFs are very promising biomaterials for wound care, especially CS_PEO@P_C.

Men who stare at bone: multimodal monitoring of bone healing.

Knowledge of the physiological and pathological processes, taking place in bone during fracture healing or defect regeneration, is essential in order to develop strategies to enhance bone healing under normal and critical conditions. Preclinical testing allows a wide range of imaging modalities that may be applied both simultaneously and longitudinally, which will in turn lower the number of animals needed to allow a comprehensive assessment of the healing process. This work provides an up-to-date review on morphological, functional, optical, biochemical, and biophysical imaging techniques including their advantages, disadvantages and potential for combining them in a multimodal and multiscale manner. The focus lies on preclinical testing of biomaterials modified with artificial extracellular matrices in various animal models to enhance bone remodeling and regeneration.

Design of Intelligent Interface Based on Cytocompatible Polymers for Control on Cell Function

Bioinspired polymeric biomaterials with excellent cytocompatibility have been designed in this study. 2-Methacryloyloxyehtyl phosphorylcholine (MPC) is a phospholipid polymer and an essential polymeric biomaterial, which has been used in various biomedical and pharmaceutical applications including implantable medical devices. Furthermore, it is a methacrylate monomer unit and can be copolymerized with other vinyl monomers via conventional radical polymerization. The water-solubility of MPC polymers depends on the molecular composition and molecular weight of the polymers. PMB is a water-soluble polymer copolymerized with hydrophobic n-butyl methacrylate, and can be used as a solubilizing agent for poorly soluble drugs. The phospholipid polymers showed low cytotoxicity, and the solubilized drugs effectively not only penetrated into the cells but also into the surrounding tissues. In addition, the water-soluble MPC polymer containing a phenylboronic acid moiety was observed to spontaneously form polymeric hydrogels with polyol compounds. The reversible polymer hydrogels were used as artificial extracellular matrices for cell immobilization and cell engineering. Polymeric biomaterials with intelligent interfaces might be explored as innovative techniques for application in pharmaceutical and life sciences.