Personalized medicine for reconstruction of critical-size bone defects – a translational approach with customizable vascularized bone tissue

Kengelbach‐Weigand, Annika; Thielen, Carolina; Bäuerle, Tobias; Götzl, Rebekka; Gerber, Thomas; Körner, Carolin; Beier, Justus P.; Horch, Raymund E.; Boos, Anja M.

doi:10.1038/s41536-021-00158-8

Cited by 29 publications

(24 citation statements)

References 46 publications

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“…In the latter case, matrix-encapsulated, proliferating producer cells should be injected or implanted locally for long-term production of a biological directly at the target tissue of interest . In this concept, an appropriate pre-vascularization is helpful for clinical translation to maintain sufficient vascularity of any therapeutic constructs . Furthermore, another crucial factor for therapeutic protein delivery is the used cell type, as stable protein expression, successful scale-up, and long-term production should be guaranteed. , …”

Section: Introductionmentioning

confidence: 99%

Recombinant Spider Silk Bioinks for Continuous Protein Release by Encapsulated Producer Cells

et al. 2022

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Targeted therapies using biopharmaceuticals are of growing clinical importance in disease treatment. Currently, there are several limitations of protein-based therapeutics (biologicals), including suboptimal biodistribution, lack of stability, and systemic side effects. A promising approach to overcoming these limitations could be a therapeutic cell-loaded 3D construct consisting of a suitable matrix component that harbors producer cells continuously secreting the biological of interest. Here, the recombinant spider silk proteins eADF4(C16), eADF4(C16)-RGD, and eADF4(C16)-RGE have been processed together with HEK293 producer cells stably secreting the highly traceable reporter biological TNFR2-Fc-GpL, a fusion protein consisting of the extracellular domain of TNFR2, the Fc domain of human IgG1, and the luciferase of Gaussia princeps as a reporter domain. eADF4(C16) and eADF4(C16)-RGD hydrogels provide structural and mechanical support, promote HEK293 cell growth, and allow fusion protein production by the latter. Bioink-captured HEK293 producer cells continuously release functional TNFR2-Fc-GpL over 14 days. Thus, the combination of biocompatible, printable spider silk bioinks with drug-producing cells is promising for generating implantable 3D constructs for continuous targeted therapy.

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Section: Introductionmentioning

confidence: 99%

Recombinant Spider Silk Bioinks for Continuous Protein Release by Encapsulated Producer Cells

et al. 2022

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“…In this study, CM from a human ADSC cell line was used. Patient-dependent individual factors, such as high age, adiposity, comorbidities, or possible treatments could have a negative effect on ADSC's regenerative potential to grow and differentiate and therefore on their secretome [10,[39][40][41][42]. There still is the need for further experiments with ADSCs from different patients to analyze their interindividual differences, their impact on ADSC behavior [43,44], and, in a next step, their influence on wound healing.…”

Section: Discussionmentioning

confidence: 99%

IGF-I and Hyaluronic Acid Mitigate the Negative Effect of Irradiation on Human Skin Keratinocytes

Sörgel

Schmid

Stadelmann

et al. 2022

Cancers

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Ionizing radiation has become an integral part of modern cancer therapy regimens. Various side effects, such as radiation dermatitis, affect patients in acute and chronic forms and decrease therapy compliance significantly. In this study, primary keratinocytes were irradiated in a 2-dimensional (2D) culture as well as on a 3-dimensional (3D) collagen-elastin matrix with doses of 2 and 5 Gy. The effect of different concentrations of IGF-I, KGF, platelet lysate (PL), high and low molecular weight hyaluronic acid (H-HA, L-HA), and adipose-derived stem cell (ADSC) conditioned medium was analyzed in respect to cell viability (WST-8), wound closure (migration), and the gene expression (quantitative real-time PCR) of 2D cultures. The 3D culture was evaluated by WST-8. A mixture of H-HA and L-HA, as well as IGF-I, could significantly stimulate the keratinocyte viability and migration which were severely reduced by irradiation. The MKI67and IL6 gene expression of irradiated keratinocytes was significantly higher after H-HA/L-HA treatment. The stimulating effects of H-HA/L-HA and IGF-I were able to be confirmed in 3D culture. A positive influence on cell viability, migration, and gene expression was achieved after the treatment with H-L-HA and IGF-I. These results open the possibility of a novel therapeutic method for both the prevention and the treatment of radiation dermatitis.

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“…This field has advanced greatly in recent years. New advanced technologies of bioadditive manufacturing allow the construction of structures closer in architecture to bone tissue [24]. However, many of the biogels used to create 3D cultures contain substances that are not approved for clinical use.…”

Section: Discussionmentioning

confidence: 99%

Three-Dimensional Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells Promotes Matrix Metallopeptidase 13 (MMP13) Expression in Type I Collagen Hydrogels

Anerillas

Kingham

Wiberg

et al. 2021

IJMS

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Autologous bone transplantation is the principal method for reconstruction of large bone defects. This technique has limitations, such as donor site availability, amount of bone needed and morbidity. An alternative to this technique is tissue engineering with bone marrow-derived mesenchymal stem cells (BMSCs). In this study, our aim was to elucidate the benefits of culturing BMSCs in 3D compared with the traditional 2D culture. In an initial screening, we combined BMSCs with four different biogels: unmodified type I collagen (Col I), type I collagen methacrylate (ColMa), an alginate and cellulose-based bioink (CELLINK) and a gelatin-based bioink containing xanthan gum (GelXA-bone). Col I was the best for structural integrity and maintenance of cell morphology. Osteogenic, adipogenic, and chondrogenic differentiations of the BMSCs in 2D versus 3D type I collagen gels were investigated. While the traditional pellet culture for chondrogenesis was superior to our tested 3D culture, Col I hydrogels (i.e., 3D) favored adipogenic and osteogenic differentiation. Further focus of this study on osteogenesis were conducted by comparing 2D and 3D differentiated BMSCs with Osteoimage® (stains hydroxyapatite), von Kossa (stains anionic portion of phosphates, carbonates, and other salts) and Alizarin Red (stains Ca2+ deposits). Multivariate gene analysis with various covariates showed low variability among donors, successful osteogenic differentiation, and the identification of one gene (matrix metallopeptidase 13, MMP13) significantly differentially expressed in 2D vs. 3D cultures. MMP13 protein expression was confirmed with immunohistochemistry. In conclusion, this study shows evidence for the suitability of type I collagen gels for 3D osteogenic differentiation of BMSCs, which might improve the production of tissue-engineered constructs for treatment of bone defects.

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Personalized medicine for reconstruction of critical-size bone defects – a translational approach with customizable vascularized bone tissue

Cited by 29 publications

References 46 publications

Recombinant Spider Silk Bioinks for Continuous Protein Release by Encapsulated Producer Cells

Recombinant Spider Silk Bioinks for Continuous Protein Release by Encapsulated Producer Cells

IGF-I and Hyaluronic Acid Mitigate the Negative Effect of Irradiation on Human Skin Keratinocytes

Three-Dimensional Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells Promotes Matrix Metallopeptidase 13 (MMP13) Expression in Type I Collagen Hydrogels

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