Micro- and nanoengineering approaches to control stem cell-biomaterial interactions.

As our population ages, there is a greater need for a suitable supply of engineered tissues to address a range of debilitating ailments. Stem cell based therapies are envisioned to meet this emerging need. Despite significant progress in controlling stem cell differentiation, it is still difficult to engineer human tissue constructs for transplantation. Recent advances in micro- and nanofabrication techniques have enabled the design of more biomimetic biomaterials that may be used to direct the fate of stem cells. These biomaterials could have a significant impact on the next generation of stem cell based therapies. Here, we highlight the recent progress made by micro- and nanoengineering techniques in the biomaterials field in the context of directing stem cell differentiation. Particular attention is given to the effect of surface topography, chemistry, mechanics and micro- and nanopatterns on the differentiation of embryonic, mesenchymal and neural stem cells

Micro- and Nanoengineering Approaches to Control Stem Cell-Biomaterial Interactions

As our population ages, there is a greater need for a suitable supply of engineered tissues to address a range of debilitating ailments. Stem cell based therapies are envisioned to meet this emerging need. Despite significant progress in controlling stem cell differentiation, it is still difficult to engineer human tissue constructs for transplantation. Recent advances in micro- and nanofabrication techniques have enabled the design of more biomimetic biomaterials that may be used to direct the fate of stem cells. These biomaterials could have a significant impact on the next generation of stem cell based therapies. Here, we highlight the recent progress made by micro- and nanoengineering techniques in the biomaterials field in the context of directing stem cell differentiation. Particular attention is given to the effect of surface topography, chemistry, mechanics and micro- and nanopatterns on the differentiation of embryonic, mesenchymal and neural stem cells

Engineering complex tissue-like microgel arrays for evaluating stem cell differentiation

Development of tissue engineering scaffolds with native-like biology and microarchitectures is a prerequisite for stem cell mediated generation of off-the-shelf-tissues. So far, the field of tissue engineering has not full-filled its grand potential of engineering such combinatorial scaffolds for engineering functional tissues. This is primarily due to the many challenges associated with finding the right microarchitectures and ECM compositions for optimal tissue regeneration. Here, we have developed a new microgel array to address this grand challenge through robotic printing of complex stem cell-laden microgel arrays. The developed microgel array platform consisted of various microgel environments that where composed of native-like cellular microarchitectures resembling vascularized and bone marrow tissue architectures. The feasibility of our array system was demonstrated through localized cell spreading and osteogenic differentiation of human mesenchymal stem cells (hMSCs) into complex tissue-like structures. In summary, we have developed a tissue-like microgel array for evaluating stem cell differentiation within complex and heterogeneous cell microenvironments. We anticipate that the developed platform will be used for high-throughput identification of combinatorial and native-like scaffolds for tissue engineering of functional organs

Design and Manufacture of Bone Cements Based on Calcium Sulfate Hemihydrate and Mg, Sr-Doped Bioactive Glass

In the present study, a novel composite bone cement based on calcium sulfate hemihydrate (CSH) and Mg, Sr-containing bioactive glass (BG) as solid phase, and solution of chitosan as liquid phase were developed. The phase composition, morphology, setting time, injectability, viscosity, and cellular responses of the composites with various contents of BG (0, 10, 20, and 30 wt.%) were investigated. The pure calcium sulfate cement was set at approximately 180 min, whereas the setting time was drastically decreased to 6 min by replacing 30 wt.% glass powder for CSH in the cement solid phase. BG changed the microscopic morphology of the set cement and decreased the size and compaction of the precipitated gypsum phase. Replacing the CSH phase with BG increased injection force of the produced cement; however, all the cements were injected at a nearly constant force, lower than 20 N. The viscosity measurements in oscillatory mode determined the shear-thinning behavior of the pastes. Although the viscosity of the pastes increased with increasing BG content, it was influenced by the frequency extent. Pure calcium sulfate cement exhibited some transient cytotoxicity on human-derived bone mesenchymal stem cells and it was compensated by introducing BG phase. Moreover, BG improved the cell proliferation and mineralization of extracellular matrix as shown by calcein measurements. The results indicate the injectable composite cement comprising 70 wt.% CSH and 30 wt.% Mg, Sr-doped BG has better setting, mechanical and cellular behaviors and hence, is a potential candidate for bone repair, however more animal and human clinical evaluations are essential.The present work was financially supported by Materials and Energy Research Center (MERC, Karaj, Iran) through grant No. 781399055. The APC was funded by Alireza Dolatshahi-Pirouz

Reinforcement of Calcium Phosphate Cement with Hybrid Silk Fibroin/Kappa-Carrageenan Nanofibers

Calcium phosphate cements (CPCs) offer a promising solution for treating bone defects due to their osteoconductive, injectable, biocompatible, and bone replacement properties. However, their brittle nature restricts their utilization to non-load-bearing applications. In this study, the impact of hybrid silk fibroin (SF) and kappa-carrageenan (k-CG) nanofibers as reinforcements in CPC was investigated. The CPC composite was fabricated by incorporating electrospun nanofibers in 1, 3, and 5% volume fractions. The morphology, mineralization, mechanical properties, setting time, injectability, cell adhesion, and mineralization of the CPC composites were analyzed. The results demonstrated that the addition of the nanofibers improved the CPC mixture, leading to an increase in compressive strength (14.8 ± 0.3 MPa compared to 8.1 ± 0.4 MPa of the unreinforced CPC). Similar improvements were seen in the bending strength and work fracture (WOF). The MC3T3-E1 cell culture experiments indicated that cells attached well to the surfaces of all cement samples and tended to join their adjacent cells. Additionally, the CPC composites showed higher cell mineralization after a culture period of 14 days, indicating that the SF/k-CG combination has potential for applications as a CPC reinforcement and bone cell regeneration promoter

Advances in cell-laden hydrogels for delivering therapeutics

Almost six decades ago, a visionary scientist reported a new method for encapsulating aqueous solutions of protein within semipermeable polymer membranes [1]. This approach was successfully tested in the 1970s and 1980s by immobilizing xenograft islet cells to control glucose metabolism in small animal models [2,3]. Since then, the concept of cell-laden hydrogels has evolved and progressed but still those pioneering works are perfect examples of the theoretical advantages that this approach may offer in terms of long-term delivery and immune protection [4]. In its most basic form, cell-laden hydrogels or bioartificial organs consist of a polymeric or synthetic membrane structure that entraps a wide range of cells releasing bioactive drugs or proteins [5,6]. The three-dimensional (3D) constructs, typically either shaped as a microcapsule or a hollow-fiber, will regulate with different efficiency the permeability and mechanical stability of the cell-based medicine [7]. The semipermeable membrane is responsible for preventing high molecular weight molecules, antibodies and other immunologic components from entering within the construct but also controls the inward/outward diffusion of critical agents for cell survival and therapeutic efficacy including nutrients, oxygen, waste agents and therapeutic protein products (Figure 1). Even though the journey from theory to practice has been demanding and challenging, recent progress in the field is creating new avenues of hope to use this approach in several unmet clinical needs ranging from diabetes to ophthalmological disorders or rare diseases

Smart alginate inks for tissue engineering applications

Amazing achievements have been made in the field of tissue engineering during the past decades. However, we have not yet seen fully functional human heart, liver, brain, or kidney tissue emerge from the clinics. The promise of tissue engineering is thus still not fully unleashed. This is mainly related to the challenges associated with producing tissue constructs with similar complexity as native tissue. Bioprinting is an innovative technology that has been used to obliterate these obstacles. Nevertheless, natural organs are highly dynamic and can change shape over time; this is part of their functional repertoire inside the body. 3D-bioprinted tissue constructs should likewise adapt to their surrounding environment and not remain static. For this reason, the new trend in the field is 4D bioprinting – a new method that delivers printed constructs that can evolve their shape and function over time. A key lack of methodology for printing approaches is the scalability, easy-to-print, and intelligent inks. Alginate plays a vital role in driving innovative progress in 3D and 4D bioprinting due to its exceptional properties, scalability, and versatility. Alginate's ability to support 3D and 4D printing methods positions it as a key material for fueling advancements in bioprinting across various applications, from tissue engineering to regenerative medicine and beyond. Here, we review the current progress in designing scalable alginate (Alg) bioinks for 3D and 4D bioprinting in a "dry"/air state. Our focus is primarily on tissue engineering, however, these next-generation materials could be used in the emerging fields of soft robotics, bioelectronics, and cyborganics.</p