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Current research on surface modifications has yielded advanced implant biomaterials. Various implant surface modifications have been shown to be promising in improving bone target cell response, but more comprehensive studies whether certain implant surface modifications can directly target cell behavioural features such as morphogenesis and proliferation are needed. Here, we studied the response of primary alveolar bone cells on various implant surface modifications in terms of osteoblast morphology and proliferation in vitro. Analyses of surface modifications led to surface-related test parameters including the topographical parameters micro-roughness, texture aspect and surface enlargement as well as the physicochemical parameter surface wettability. We compared osteoblast morphology and proliferation towards the above-mentioned parameters and found that texture aspect and surface enlargement but not surface roughness or wettability exhibited significant impact on osteoblast morphology and proliferation. Detailed analysis revealed osteoblast proliferation as a function of cell morphology, substantiated by an osteoblast size- and morphology-dependent increase in mitotic activity. These findings show that implant surface topography controls cell behavioural morphology and subsequently cell proliferation, thereby opening the road for cell instructive biomaterials.

Plasma-treatment of oral implant biomaterials prior to clinical insertion is envisaged as a potential surface modification method for enhanced implant healing. To investigate a putative effect of plasma-functionalized implant biomaterials on oral tissue cells, this investigation examined the response of alveolar bone osteoblasts and gingival fibroblasts to clinically established zirconia- and titanium-based implant surfaces for bone and soft tissue integration. The biomaterials were either functionalized with oxygen-plasma in a plasma-cleaner or left untreated as controls, and were characterized in terms of topography and wettability. For the biological evaluation, the cell adhesion, morphogenesis, metabolic activity and proliferation were examined, since these parameters are closely interconnected during cell-biomaterial interaction. The results revealed that plasma-functionalization increased implant surface wettability. The magnitude of this effect thereby depended on surface topography parameters and initial wettability of the biomaterials. Concerning the cell response, plasma-functionalization of smooth surfaces affected initial fibroblast morphogenesis, whereas osteoblast morphology on rough surfaces was mainly influenced by topography. The plasma- and topography-induced differential cell morphologies were however not strong enough to trigger a change in proliferation behaviour. Hence, the results indicate that oxygen plasma-functionalization represents a possible cytocompatible implant surface modification method which can be applied for tailoring implant surface wettability.

Allogenic transplants of the cornea are prone to rejection, especially in repetitive transplantation and in scarred or highly vascularized recipient sites. Patients with these ailments would particularly benefit from the possibility to use non-immunogenic decellularized tissue scaffolds for transplantation, which may be repopulated by host cells in situ or in vitro. So, the aim of this study was to develop a fast and efficient decellularization method for creating a human corneal extracellular matrix scaffold suitable for repopulation with human cells from the corneal limbus. To decellularize human donor corneas, sodium deoxycholate, deoxyribonuclease I, and dextran were assessed to remove cells and nuclei and to control tissue swelling, respectively. We evaluated the decellularization effects on the ultrastructure, optical, mechanical, and biological properties of the human cornea. Scaffold recellularization was studied using primary human limbal epithelial cells, stromal cells, and melanocytes in vitro and a lamellar transplantation approach ex vivo. Our data strongly suggest that this approach allowed the effective removal of cellular and nuclear material in a very short period of time while preserving extracellular matrix proteins, glycosaminoglycans, tissue structure, and optical transmission properties. In vitro recellularization demonstrated good biocompatibility of the decellularized human cornea and ex vivo transplantation revealed complete epithelialization and stromal repopulation from the host tissue. Thus, the generated decellularized human corneal scaffold could be a promising biological material for anterior corneal reconstruction in the treatment of corneal defects.

This paper presents a material programming approach for designing 4D‐printed self‐shaping material systems based on biological role models. Plants have inspired numerous adaptive systems that move without using any operating energy; however, these systems are typically designed and fabricated in the form of simplified bilayers. This work introduces computational design methods for 4D‐printing bio‐inspired behaviors with compounded mechanisms. To emulate the anisotropic arrangement of motile plant structures, material systems are tailored at the mesoscale using extrusion‐based 3D‐printing. The methodology is demonstrated by transferring the principle of force generation by a twining plant (Dioscorea bulbifera) to the application of a self‐tightening splint. Through the tensioning of its stem helix, D. bulbifera exhibits a squeezing force on its support to provide stability against gravity. The functional strategies of D. bulbifera are ed and translated to customized 4D‐printed material systems. The squeezing forces of these bio‐inspired motion mechanisms are then evaluated. Finally, the function of self‐tightening is prototyped in a wrist‐forearm splint—a common orthotic device for alignment. The presented approach enables the transfer of novel and expanded biomimetic design strategies to 4D‐printed motion mechanisms, further opening the design space to new types of adaptive creations for wearable assistive technologies and beyond. This paper presents a design and material programming approach for adaptive material systems through a case study of biomimetic design. The twining air potato (Dioscorea bulbifera) provides stability against gravity by tensioning its stem helix and generating a squeezing force. Based on D. bulbifera's force generation, 4D‐printing is employed to produce adaptive wearable systems with passive, targeted shape changes.

Extrusion-based printing enables simplified and economic manufacturing of surgical guides for oral implant placement. Therefore, the cytotoxicity of a biocopolyester (BE) and a polypropylene (PP), intended for the fused filament fabrication of surgical guides was evaluated. For comparison, a medically certified resin based on methacrylic esters (ME) was printed by stereolithography (n = 18 each group). Human gingival keratinocytes (HGK) were exposed to eluates of the tested materials and an impedance measurement and a tetrazolium assay (MTT) were performed. Modulations in gene expression were analyzed by quantitative PCR. One-way ANOVA with post-hoc Tukey tests were applied. None of the materials exceeded the threshold for cytotoxicity (< 70% viability in MTT) according to ISO 10993-5:2009. The impedance-based cell indices for PP and BE, reflecting cell proliferation, showed little deviations from the control, while ME caused a reduction of up to 45% after 72 h. PCR analysis after 72 h revealed only marginal modulations caused by BE while PP induced a down-regulation of genes encoding for inflammation and apoptosis ( p  < 0.05). In contrast, the 72 h ME eluate caused an up-regulation of these genes ( p  < 0.01). All evaluated materials can be considered biocompatible in vitro for short-term application. However, long-term contact to ME might induce (pro-)apoptotic/(pro-)inflammatory responses in HGK.

We explored the potential of poly(oxonorbornene)-based synthetic mimics of antimicrobial peptides (SMAMPs), a promising new class of antimicrobial polymers with cell-selectivity and low resistance development potential, for clinical applications. We evaluated their antimicrobial activity against a panel of seven clinical and regulatory relevant bacteria strains, and tested their toxicity with two different kinds of primary human cells. For the antimicrobial activity, we performed the minimum inhibitory concentration (MIC) assay and determined the minimum bactericidal concentration (MBC) according to the NCCLS guidelines. The results revealed specific problems that may occur when testing the antimicrobial activity of amphiphilic cationic polymers, and confirmed the working hypothesis that the more hydrophilic SMAMP polymers in our portfolio were 'doubly selective', i.e. they are not only selective for bacteria over mammalian cells, but also for Gram-positive over Gram-negative bacteria. The data also showed that we could improve the broad-band activity of one SMAMP, and in combination with the results from the cell toxicity experiments, identified this polymer as a promising candidate for further in-vitro and in-vivo testing. Transmission electron studies revealed that the cellular envelopes of both E. coli and S. aureus were severely damaged due to SMAMP action on the bacterial membrane, which strengthened the argument that SMAMPs closely resemble antimicrobial peptides. To test cell toxicity, we used the traditional hemolysis assay with human red blood cells, and the novel xCelligence assay with primary human fibroblasts. The data reported here is the first example in which a hemolysis assay is benchmarked against the xCelligence assay. It revealed that the same trends were obtained using these complementary methods. This establishes the xCelligence assay with primary human cells as a useful tool for SMAMP characterization.

Although cytoplasmic intermediate filaments (cIFs) are essential for cell physiology, the molecular and cell functional consequences of cIF disturbances are poorly understood. Identifying defaults in cell function-controlled tissue homeostasis and understanding the interrelationship between specific cIFs and distinct cell functions remain key challenges. Using an RNAi-based mechanistic approach, we connected the impairment of cell-inherent cIFs with molecular and cell functional consequences, such as proliferation and differentiation. To investigate cIF disruption consequences in the oral epithelium, different cell transformation stages, originating from alcohol-treated oral gingival keratinocytes, were used. We found that impairment of keratin (KRT) KRT5, KRT14 and vimentin (VIM) affects proliferation and differentiation, and modulates the chromatin status. Furthermore, cIF impairment reduces the expression of nuclear integrity participant lamin B1 and the terminal keratinocyte differentiation marker involucrin (IVL). Conversely, impairment of IVL reduces cIF expression levels, functionally suggesting a regulatory interaction between cIFs and IVL. The findings demonstrate that the impairment of cIFs leads to imbalances in proliferation and differentiation, both of which are essential for tissue homeostasis. Thus, targeted impairment of cIFs appears promising to investigate the functional role of cIFs on cell-dependent tissue physiology at the molecular level and identifies putative interactions of cIFs with epithelial differentiation.

Early molecular events underlying ethanol-induced oral squamous cell carcinoma development remain insufficiently understood, primarily due to a lack of suitable in vitro systems that recapitulate the initial stages of premalignant transformation. Therefore, a cell culture model of human gingival keratinocytes representing progressive stages of early ethanol-induced cell transformation was established and comprehensively characterized. The three cell lines, named “gingival keratinocytes” (GK), “epithelioid” (EPI) and “fibroblastoid” (FIB), and their derivatives were analyzed by morphological, cell biological and biochemical methods, with an emphasis on epithelial-to-mesenchymal transition (EMT)-related signaling pathways. All cell lines were non-tumorigenic in vitro. Chronic ethanol exposure induced distinct morphological and molecular alterations that capture early premalignant changes in vitro. This includes reduced E-Cadherin and enhanced Vimentin expression, accompanied by an increased production of reactive oxygen species. Notably, even morphologically stable cell lines displayed metabolic susceptibility to EMT induction, indicating the early activation of transformation-associated signaling cascades even in a premalignant state. These alterations, however, closely mirrored pathohistological features of oral squamous cell carcinomas such as loss of epithelial integrity and acquisition of mesenchymal characteristics. Collectively, the presented model provides a robust and accessible in vitro platform for investigating very early ethanol-induced oral carcinogenesis mechanisms that are relevant in a premalignant state and may facilitate the identification of diagnostic and preventive biomarkers to improve patient outcomes in alcohol-associated oral cancer and precursor lesions.

The escalating prevalence of anterior cruciate ligament (ACL) injuries in sports necessitates innovative strategies for ACL reconstruction. In this study, we propose a multiphasic bone-ligament-bone (BLB) integrated scaffold as a potential solution. The BLB scaffold comprised two polylactic acid (PLA)/deferoxamine (DFO)@mesoporous hydroxyapatite (MHA) thermally induced phase separation (TIPS) scaffolds bridged by silk fibroin (SF)/connective tissue growth factor (CTGF)@Poly(l-lactide-co-ε-caprolactone) (PLCL) nanofiber yarn braided scaffold. This combination mimics the native architecture of the ACL tissue. The mechanical properties of the BLB scaffolds were determined to be compatible with the human ACL. In vitro experiments demonstrated that CTGF induced the expression of ligament-related genes, while TIPS scaffolds loaded with MHA and DFO enhanced the osteogenic-related gene expression of bone marrow stem cells (BMSCs) and promoted the migration and tubular formation of human umbilical vein endothelial cells (HUVECs). In rabbit models, the BLB scaffold efficiently facilitated ligamentization and graft-bone integration processes by providing bioactive substances. The double delivery of DFO and calcium ions by the BLB scaffold synergistically promoted bone regeneration, while CTGF improved collagen formation and ligament healing. Collectively, the findings indicate that the BLB scaffold exhibits substantial promise for ACL reconstruction. Additional investigation and advancement of this scaffold may yield enhanced results in the management of ACL injuries. [Display omitted] •The multiphasic BLB integrated scaffold's architecture closely resembles the native ACL tissue, promoting ACL regeneration.•The mechanical properties of the BLB scaffolds were determined to be compatible with the human ACL.•The BLB scaffolds show excellent biocompatibility and bioactivity, with no adverse reactions observed in animal models.•BLB scaffold efficiently facilitated ligamentization and graft-bone integration processes by providing bioactive substances.

Among oral tissues, the periodontium is permanently subjected to mechanical forces resulting from chewing, mastication, or orthodontic appliances. Molecularly, these movements induce a series of subsequent signaling processes, which are embedded in the biological concept of cellular mechanotransduction (MT). Cell and tissue structures, ranging from the extracellular matrix (ECM) to the plasma membrane, the cytosol and the nucleus, are involved in MT. Dysregulation of the diverse, fine-tuned interaction of molecular players responsible for transmitting biophysical environmental information into the cell’s inner milieu can lead to and promote serious diseases, such as periodontitis or oral squamous cell carcinoma (OSCC). Therefore, periodontal integrity and regeneration is highly dependent on the proper integration and regulation of mechanobiological signals in the context of cell behavior. Recent experimental findings have increased the understanding of classical cellular mechanosensing mechanisms by both integrating exogenic factors such as bacterial gingipain proteases and newly discovered cell-inherent functions of mechanoresponsive co-transcriptional regulators such as the Yes-associated protein 1 (YAP1) or the nuclear cytoskeleton. Regarding periodontal MT research, this review offers insights into the current trends and open aspects. Concerning oral regenerative medicine or weakening of periodontal tissue diseases, perspectives on future applications of mechanobiological principles are discussed.