Biological Biomaterials for Regenerative Medicine

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological and Bio- Materials".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 36434

Special Issue Editors

Department of Industrial Engineering, BIOtech Research Center, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Interests: scaffolds design; regenerative medicine; nature-derived matrices; polymers functionalization; cells; tissue engineering; stem cell culture; cell culture; biocompatibility evaluations; bioink design; drug release systems; 3D in vitro models
Special Issues, Collections and Topics in MDPI journals
University of Minho, I3B's - Research Institute on Biomaterials, Biodegradables and Biomimetics, Guimarães, Portugal
Interests: biodegradable biomaterials; polymer science; porous biomaterials; natural origin biomaterials; surface biofunctionalization of biomaterials; nanostructured biomaterials and composites; bone and cartilage tissue engineering; adult stem cells; advanced therapies; regenerative medicine; animal models for testing of biomaterials
Special Issues, Collections and Topics in MDPI journals
3B’s Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Barco, Portugal
Interests: nanomedicine; inflammatory diseases; cancer; biomaterials; nanotechnology; materials engineering and chemistry; advanced therapies; tissue engineering; regenerative medicine
Special Issues, Collections and Topics in MDPI journals
1. 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805-017 Guimarães, Portugal
2. ICVS/3B’s–PT Government Associate Laboratory, Braga, 4805-017 Guimarães, Portugal
Interests: tissue engineering; regenerative medicine; biomaterials; biomimetics; biodegradable materials; 3D in vitro models; cancer modelling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Biologically derived biomaterials present unique and well-designed molecular structures with intrinsic affinities to the complex networks involved in tissue homeostasis. Consequently, biomaterial-based engineering approaches hold tremendous potential to regenerate tissues and organs damaged by trauma or disease. The rational design of those biomaterial substrates with adequate structural (e.g., surface topography, size, and shape) and/or chemical (e.g., drugs and cell signaling molecules) cues will allow driving homeostasis and functional tissue regeneration. Indeed, the ability of the engineered substrates to combine the function and fate of endogenous (e.g., endothelial and immune cells) and exogenous stem or progenitor cells can advance tissue engineering therapies into routine clinical practice.

The aim of this Special Issue is to publish original research articles in advanced and effective regenerative medicine strategies. Review articles critically and systematically treating the published research and forecasting future avenues in the field and highlighting the current challenges that hinder the translation of regenerative medicine strategies into clinical practice will be considered for inclusion in this Special Issue.

Prof. Dr. Antonella Motta
Prof. Dr. Rui L. Reis
Prof. Dr. Nuno M. Neves
Dr. Helena Ferreira
Guest Editors

Manuscript Submission Information

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Keywords

  • biomaterials
  • nature-derived materials
  • regenerative medicine
  • tissue engineering
  • advanced materials engineering strategies
  • stem cells
  • cell signaling biomolecules
  • controlled release systems
  • 3D in vitro models
  • advanced imaging
  • sustainable materials (Remix)
  • nature derived materials (Remix)

Published Papers (11 papers)

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Research

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13 pages, 4186 KiB  
Article
Tropoelastin Promotes the Formation of Dense, Interconnected Endothelial Networks
Biomolecules 2021, 11(9), 1318; https://doi.org/10.3390/biom11091318 - 06 Sep 2021
Cited by 4 | Viewed by 2117
Abstract
Tropoelastin, the soluble precursor of elastin, has been used for regenerative and wound healing purposes and noted for its ability to accelerate wound repair by enhancing vascularization at the site of implantation. However, it is not clear whether these effects are directly due [...] Read more.
Tropoelastin, the soluble precursor of elastin, has been used for regenerative and wound healing purposes and noted for its ability to accelerate wound repair by enhancing vascularization at the site of implantation. However, it is not clear whether these effects are directly due to the interaction of tropoelastin with endothelial cells or communicated to endothelial cells following interactions between tropoelastin and neighboring cells, such as mesenchymal stem cells (MSCs). We adapted an endothelial tube formation assay to model in vivo vascularization with the goal of exploring the stimulatory mechanism of tropoelastin. In the presence of tropoelastin, endothelial cells formed less tubes, with reduced spreading into capillary-like networks. In contrast, conditioned media from MSCs that had been cultured on tropoelastin enhanced the formation of more dense, complex, and interconnected endothelial tube networks. This pro-angiogenic effect of tropoelastin is mediated indirectly through the action of tropoelastin on co-cultured cells. We conclude that tropoelastin inhibits endothelial tube formation, and that this effect is reversed by pro-angiogenic crosstalk from tropoelastin-treated MSCs. Furthermore, we find that the known in vivo pro-angiogenic effects of tropoelastin can be modeled in vitro, highlighting the value of tropoelastin as an indirect mediator of angiogenesis. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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17 pages, 3903 KiB  
Article
Development and Evaluation of Gellan Gum/Silk Fibroin/Chondroitin Sulfate Ternary Injectable Hydrogel for Cartilage Tissue Engineering
Biomolecules 2021, 11(8), 1184; https://doi.org/10.3390/biom11081184 - 11 Aug 2021
Cited by 25 | Viewed by 3860
Abstract
Hydrogel is in the spotlight as a useful biomaterial in the field of drug delivery and tissue engineering due to its similar biological properties to a native extracellular matrix (ECM). Herein, we proposed a ternary hydrogel of gellan gum (GG), silk fibroin (SF), [...] Read more.
Hydrogel is in the spotlight as a useful biomaterial in the field of drug delivery and tissue engineering due to its similar biological properties to a native extracellular matrix (ECM). Herein, we proposed a ternary hydrogel of gellan gum (GG), silk fibroin (SF), and chondroitin sulfate (CS) as a biomaterial for cartilage tissue engineering. The hydrogels were fabricated with a facile combination of the physical and chemical crosslinking method. The purpose of this study was to find the proper content of SF and GG for the ternary matrix and confirm the applicability of the hydrogel in vitro and in vivo. The chemical and mechanical properties were measured to confirm the suitability of the hydrogel for cartilage tissue engineering. The biocompatibility of the hydrogels was investigated by analyzing the cell morphology, adhesion, proliferation, migration, and growth of articular chondrocytes-laden hydrogels. The results showed that the higher proportion of GG enhanced the mechanical properties of the hydrogel but the groups with over 0.75% of GG exhibited gelling temperatures over 40 °C, which was a harsh condition for cell encapsulation. The 0.3% GG/3.7% SF/CS and 0.5% GG/3.5% SF/CS hydrogels were chosen for the in vitro study. The cells that were encapsulated in the hydrogels did not show any abnormalities and exhibited low cytotoxicity. The biochemical properties and gene expression of the encapsulated cells exhibited positive cell growth and expression of cartilage-specific ECM and genes in the 0.5% GG/3.5% SF/CS hydrogel. Overall, the study of the GG/SF/CS ternary hydrogel with an appropriate content showed that the combination of GG, SF, and CS can synergistically promote articular cartilage defect repair and has considerable potential for application as a biomaterial in cartilage tissue engineering. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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14 pages, 1639 KiB  
Article
The Influence of Bloom Index, Endotoxin Levels and Polyethylene Glycol Succinimidyl Glutarate Crosslinking on the Physicochemical and Biological Properties of Gelatin Biomaterials
Biomolecules 2021, 11(7), 1003; https://doi.org/10.3390/biom11071003 - 09 Jul 2021
Cited by 5 | Viewed by 2280
Abstract
In the medical device sector, bloom index and residual endotoxins should be controlled, as they are crucial regulators of the device’s physicochemical and biological properties. It is also imperative to identify a suitable crosslinking method to increase mechanical integrity, without jeopardising cellular functions [...] Read more.
In the medical device sector, bloom index and residual endotoxins should be controlled, as they are crucial regulators of the device’s physicochemical and biological properties. It is also imperative to identify a suitable crosslinking method to increase mechanical integrity, without jeopardising cellular functions of gelatin-based devices. Herein, gelatin preparations with variable bloom index and endotoxin levels were used to fabricate non-crosslinked and polyethylene glycol succinimidyl glutarate crosslinked gelatin scaffolds, the physicochemical and biological properties of which were subsequently assessed. Gelatin preparations with low bloom index resulted in hydrogels with significantly (p < 0.05) lower compression stress, elastic modulus and resistance to enzymatic degradation, and significantly higher (p < 0.05) free amine content than gelatin preparations with high bloom index. Gelatin preparations with high endotoxin levels resulted in films that induced significantly (p < 0.05) higher macrophage clusters than gelatin preparations with low endotoxin level. Our data suggest that the bloom index modulates the physicochemical properties, and the endotoxin content regulates the biological response of gelatin biomaterials. Although polyethylene glycol succinimidyl glutarate crosslinking significantly (p < 0.05) increased compression stress, elastic modulus and resistance to enzymatic degradation, and significantly (p < 0.05) decreased free amine content, at the concentration used, it did not provide sufficient structural integrity to support cell culture. Therefore, the quest for the optimal gelatin crosslinker continues. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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16 pages, 3919 KiB  
Article
Bioinstructive Layer-by-Layer-Coated Customizable 3D Printed Perfusable Microchannels Embedded in Photocrosslinkable Hydrogels for Vascular Tissue Engineering
Biomolecules 2021, 11(6), 863; https://doi.org/10.3390/biom11060863 - 10 Jun 2021
Cited by 21 | Viewed by 3942
Abstract
The development of complex and large 3D vascularized tissue constructs remains the major goal of tissue engineering and regenerative medicine (TERM). To date, several strategies have been proposed to build functional and perfusable vascular networks in 3D tissue-engineered constructs to ensure the long-term [...] Read more.
The development of complex and large 3D vascularized tissue constructs remains the major goal of tissue engineering and regenerative medicine (TERM). To date, several strategies have been proposed to build functional and perfusable vascular networks in 3D tissue-engineered constructs to ensure the long-term cell survival and the functionality of the assembled tissues after implantation. However, none of them have been entirely successful in attaining a fully functional vascular network. Herein, we report an alternative approach to bioengineer 3D vascularized constructs by embedding bioinstructive 3D multilayered microchannels, developed by combining 3D printing with the layer-by-layer (LbL) assembly technology, in photopolymerizable hydrogels. Alginate (ALG) was chosen as the ink to produce customizable 3D sacrificial microstructures owing to its biocompatibility and structural similarity to the extracellular matrices of native tissues. ALG structures were further LbL coated with bioinstructive chitosan and arginine–glycine–aspartic acid-coupled ALG multilayers, embedded in shear-thinning photocrosslinkable xanthan gum hydrogels and exposed to a calcium-chelating solution to form perfusable multilayered microchannels, mimicking the biological barriers, such as the basement membrane, in which the endothelial cells were seeded, denoting an enhanced cell adhesion. The 3D constructs hold great promise for engineering a wide array of large-scale 3D vascularized tissue constructs for modular TERM strategies. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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16 pages, 5422 KiB  
Article
Decellularized Human Chorion Membrane as a Novel Biomaterial for Tissue Regeneration
Biomolecules 2020, 10(9), 1208; https://doi.org/10.3390/biom10091208 - 20 Aug 2020
Cited by 21 | Viewed by 2671
Abstract
Although some placenta-derived products are already used for tissue regeneration, the human chorion membrane (HCM) alone has been poorly explored. In fact, just one study uses decellularized HCM (dHCM) with native tissue architecture (i.e., without extracellular matrix (ECM) suspension creation) as a substrate [...] Read more.
Although some placenta-derived products are already used for tissue regeneration, the human chorion membrane (HCM) alone has been poorly explored. In fact, just one study uses decellularized HCM (dHCM) with native tissue architecture (i.e., without extracellular matrix (ECM) suspension creation) as a substrate for cell differentiation. The aim of this work is to fully characterize the dHCM for the presence and distribution of cell nuclei, DNA and ECM components. Moreover, mechanical properties, in vitro biological performance and in vivo biocompatibility were also studied. Our results demonstrated that the HCM was successfully decellularized and the main ECM proteins were preserved. The dHCM has two different surfaces, the reticular layer side and the trophoblast side; and is biocompatible both in vitro and in vivo. Importantly, the in vivo experiments demonstrated that on day 28 the dHCM starts to be integrated by the host tissue. Altogether, these results support the hypothesis that dHCM may be used as a biomaterial for different tissue regeneration strategies, particularly when a membrane is needed to separate tissues, organs or other biologic compartments. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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17 pages, 3146 KiB  
Article
A 3D Tissue Model of Traumatic Brain Injury with Excitotoxicity That Is Inhibited by Chronic Exposure to Gabapentinoids
Biomolecules 2020, 10(8), 1196; https://doi.org/10.3390/biom10081196 - 17 Aug 2020
Cited by 6 | Viewed by 3795
Abstract
Injury progression associated with cerebral laceration is insidious. Following the initial trauma, brain tissues become hyperexcitable, begetting further damage that compounds the initial impact over time. Clinicians have adopted several strategies to mitigate the effects of secondary brain injury; however, higher throughput screening [...] Read more.
Injury progression associated with cerebral laceration is insidious. Following the initial trauma, brain tissues become hyperexcitable, begetting further damage that compounds the initial impact over time. Clinicians have adopted several strategies to mitigate the effects of secondary brain injury; however, higher throughput screening tools with modular flexibility are needed to expedite mechanistic studies and drug discovery that will contribute to the enhanced protection, repair, and even the regeneration of neural tissues. Here we present a novel bioengineered cortical brain model of traumatic brain injury (TBI) that displays characteristics of primary and secondary injury, including an outwardly radiating cell death phenotype and increased glutamate release with excitotoxic features. DNA content and tissue function were normalized by high-concentration, chronic administrations of gabapentinoids. Additional experiments suggested that the treatment effects were likely neuroprotective rather than regenerative, as evidenced by the drug-mediated decreases in cell excitability and an absence of drug-induced proliferation. We conclude that the present model of traumatic brain injury demonstrates validity and can serve as a customizable experimental platform to assess the individual contribution of cell types on TBI progression, as well as to screen anti-excitotoxic and pro-regenerative compounds. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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14 pages, 7851 KiB  
Article
Exploring the Gelation Mechanisms and Cytocompatibility of Gold (III)-Mediated Regenerated and Thiolated Silk Fibroin Hydrogels
Biomolecules 2020, 10(3), 466; https://doi.org/10.3390/biom10030466 - 18 Mar 2020
Cited by 9 | Viewed by 3719
Abstract
Accelerating the gelation of silk fibroin (SF) solution from several days or weeks to minutes or few hours is critical for several applications (e.g., cell encapsulation, bio-ink for 3D printing, and injectable controlled release). In this study, the rapid gelation of SF induced [...] Read more.
Accelerating the gelation of silk fibroin (SF) solution from several days or weeks to minutes or few hours is critical for several applications (e.g., cell encapsulation, bio-ink for 3D printing, and injectable controlled release). In this study, the rapid gelation of SF induced by a gold salt (Au3+) as well as the cytocompatibility of Au3+-mediated SF hydrogels are reported. The gelation behaviors and mechanisms of regenerated SF and thiolated SF (tSF) were compared. Hydrogels can be obtained immediately after mixing or within three days depending on the types of silk proteins used and amount of Au3+. Au3+-mediated SF and tSF hydrogels showed different color appearances. The color of Au-SF hydrogels was purple-red, whereas the Au-tSF hydrogels maintained their initial solution color, indicating different gelation mechanisms. The reduction of Au3+ by amino groups and further reduction to Au by tyrosine present in SF, resulting in a dityrosine bonding and Au nanoparticles (NPs) production, are proposed as underlying mechanisms of Au-SF gel formation. Thiol groups of the tSF reduced Au3+ to Au+ and formed a disulfide bond, before a formation of Au+-S bonds. Protons generated during the reactions between Au3+ and SF or tSF led to a decrease of the local pH, which affected the chain aggregation of the SF, and induced the conformational transition of SF protein to beta sheet. The cytocompatibility of the Au-SF and tSF hydrogels was demonstrated by culturing with a L929 cell line, indicating that the developed hydrogels can be promising 3D matrices for different biomedical applications. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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17 pages, 3891 KiB  
Article
Photobiomodulation Therapy Associated with Heterologous Fibrin Biopolymer and Bovine Bone Matrix Helps to Reconstruct Long Bones
Biomolecules 2020, 10(3), 383; https://doi.org/10.3390/biom10030383 - 02 Mar 2020
Cited by 23 | Viewed by 3246
Abstract
Bone defects cause aesthetic and functional changes that affect the social, economic and especially the emotional life of human beings. This complication stimulates the scientific community to investigate strategies aimed at improving bone reconstruction processes using complementary therapies. Photobiomodulation therapy (PBMT) and the [...] Read more.
Bone defects cause aesthetic and functional changes that affect the social, economic and especially the emotional life of human beings. This complication stimulates the scientific community to investigate strategies aimed at improving bone reconstruction processes using complementary therapies. Photobiomodulation therapy (PBMT) and the use of new biomaterials, including heterologous fibrin biopolymer (HFB), are included in this challenge. The objective of the present study was to evaluate the influence of photobiomodulation therapy on bone tibial reconstruction of rats with biomaterial consisting of lyophilized bovine bone matrix (BM) associated or not with heterologous fibrin biopolymer. Thirty male rats were randomly separated into three groups of 10 animals. In all animals, after the anesthetic procedure, a noncritical tibial defect of 2 mm was performed. The groups received the following treatments: Group 1: BM + PBMT, Group 2: BM + HFB and Group 3: BM + HFB + PBMT. The animals from Groups 1 and 3 were submitted to PBMT in the immediate postoperative period and every 48 h until the day of euthanasia that occurred at 14 and 42 days. Analyses by computed microtomography (µCT) and histomorphometry showed statistical difference in the percentage of bone formation between Groups 3 (BM + HB + PBMT) and 2 (BM + HFB) (26.4% ± 1.03% and 20.0% ± 1.87%, respectively) at 14 days and at 42 days (38.2% ± 1.59% and 31.6% ± 1.33%, respectively), and at 42 days there was presence of bone with mature characteristics and organized connective tissue. The µCT demonstrated BM particles filling the defect and the deposition of new bone in the superficial region, especially in the ruptured cortical. It was concluded that the association of PBMT with HFB and BM has the potential to assist in the process of reconstructing bone defects in the tibia of rats. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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Review

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18 pages, 1045 KiB  
Review
Bioprinting Au Natural: The Biologics of Bioinks
Biomolecules 2021, 11(11), 1593; https://doi.org/10.3390/biom11111593 - 28 Oct 2021
Cited by 14 | Viewed by 2253
Abstract
The development of appropriate bioinks is a complex task, dependent on the mechanical and biochemical requirements of the final construct and the type of printer used for fabrication. The two most common tissue printers are micro-extrusion and digital light projection printers. Here we [...] Read more.
The development of appropriate bioinks is a complex task, dependent on the mechanical and biochemical requirements of the final construct and the type of printer used for fabrication. The two most common tissue printers are micro-extrusion and digital light projection printers. Here we briefly discuss the required characteristics of a bioink for each of these printing processes. However, physical printing is only a short window in the lifespan of a printed construct—the system must support and facilitate cellular development after it is printed. To that end, we provide a broad overview of some of the biological molecules currently used as bioinks. Each molecule has advantages for specific tissues/cells, and potential disadvantages are discussed, along with examples of their current use in the field. Notably, it is stressed that active researchers are trending towards the use of composite bioinks. Utilizing the strengths from multiple materials is highlighted as a key component of bioink development. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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15 pages, 703 KiB  
Review
Potential of Induced Pluripotent Stem Cells for Use in Gene Therapy: History, Molecular Bases, and Medical Perspectives
Biomolecules 2021, 11(5), 699; https://doi.org/10.3390/biom11050699 - 07 May 2021
Cited by 6 | Viewed by 2811
Abstract
Induced pluripotent stem cells (iPSCs) are defined as reprogrammed somatic cells exhibiting embryonic stem cell characteristics. Since their discovery in 2006, efforts have been made to utilize iPSCs in clinical settings. One of the promising fields of medicine, in which genetically patient-specific stem [...] Read more.
Induced pluripotent stem cells (iPSCs) are defined as reprogrammed somatic cells exhibiting embryonic stem cell characteristics. Since their discovery in 2006, efforts have been made to utilize iPSCs in clinical settings. One of the promising fields of medicine, in which genetically patient-specific stem cells may prove themselves useful, is gene therapy. iPSCs technology holds potential in both creating models of genetic diseases and delivering therapeutic agents into the organism via auto-transplants, which reduces the risk of rejection compared to allotransplants. However, in order to safely administer genetically corrected stem cells into patients’ tissues, efforts must be made to establish stably pluripotent stem cells and reduce the risk of insertional tumorigenesis. In order to achieve this, optimal reprogramming factors and vectors must be considered. Therefore, in this review, the molecular bases of reprogramming safe iPSCs for clinical applications and recent attempts to translate iPSCs technology into the clinical setting are discussed. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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24 pages, 2781 KiB  
Review
Pre-Clinical Evaluation of Biological Bone Substitute Materials for Application in Highly Loaded Skeletal Sites
Biomolecules 2020, 10(6), 883; https://doi.org/10.3390/biom10060883 - 09 Jun 2020
Cited by 13 | Viewed by 4022
Abstract
The development of bone substitute materials (BSMs) intended for load-bearing bone defects is highly complicated, as biological and mechanical requirements are often contradictory. In recent years, biological BSMs have been developed which allow for a more efficient integration of the material with the [...] Read more.
The development of bone substitute materials (BSMs) intended for load-bearing bone defects is highly complicated, as biological and mechanical requirements are often contradictory. In recent years, biological BSMs have been developed which allow for a more efficient integration of the material with the surrounding osseous environment and, hence, a higher mechanical stability of the treated defect. However, while these materials are promising, they are still far from ideal. Consequently, extensive preclinical experimentation is still required. The current review provides a comprehensive overview of biomechanical considerations relevant for the design of biological BSMs. Further, the preclinical evaluation of biological BSMs intended for application in highly loaded skeletal sites is discussed. The selected animal models and implantation site should mimic the pathophysiology and biomechanical loading patterns of human bone as closely as possible. In general, sheep are among the most frequently selected animal models for the evaluation of biomaterials intended for highly loaded skeletal sites. Regarding the anatomical sites, segmental bone defects created in the limbs and spinal column are suggested as the most suitable. Furthermore, the outcome measurements used to assess biological BSMs for regeneration of defects in heavily loaded bone should be relevant and straightforward. The quantitative evaluation of bone defect healing through ex vivo biomechanical tests is a valuable addition to conventional in vivo tests, as it determines the functional efficacy of BSM-induced bone healing. Finally, we conclude that further standardization of preclinical studies is essential for reliable evaluation of biological BSMs in highly loaded skeletal sites. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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