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A special issue of Journal of Functional Biomaterials (ISSN 2079-4983). This special issue belongs to the section "Bone Biomaterials".

Deadline for manuscript submissions: 10 December 2026 | Viewed by 16478

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Special Issue Editor

Dr. Xueqin Gao

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Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, 181 W Meadow Dr, Suite 1000, Vail, CO, USA
Interests: stem cells; growth factor; biomaterials; bone tissue engineering; bone biology; cartilage tissue engineering and biology; gene therapy
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Special Issue Information

Dear Colleagues,

The musculoskeletal system is vital for the movement of the human body. Non-union fractures and segmental bone defects are challenging conditions to treat in orthopedic surgery. Osteoporosis further increases the risk of fracture in older populations. Non-union fractures and segmental bone defects significantly affect patients’ quality of life and can even cause disability. Significant advancements have been achieved over the last two decades in using biomaterials to deliver stem cells, gene vectors, and functional molecules, including proteins and small molecules, for bone regeneration; however, few of these techniques have translated into new therapies in clinical practice for non-union fractures or segmental bone defects.

Therefore, the goal of this Special Issue is to unite multidisciplinary research scholars and publish research and review articles that demonstrate the recent advances in biomaterials and bone tissue engineering and repair. These include the use of biomaterials to deliver functional molecules, stem cells, exosomes, and gene expression vectors, including mRNA and 3D-printing technology, to promote bone repair. The ultimate goal is to promote new research and develop new therapies for treating bone defects.

Topics for this Special Issue include, but are not limited to, the following:

Sustained-release biomaterials or scaffolds to deliver growth factors for bone tissue engineering;
Biomaterials to deliver small molecules for bone tissue engineering;
Biomaterials to deliver stem cells for bone repair;
Biomaterials for the delivery of exosomes for bone repair;
Biomaterials to deliver functional genes for bone repair;
Three-dimensional printing of biomaterials for bone tissue engineering.

We look forward to receiving your submissions to advance research in this vital field of study.

Dr. Xueqin Gao
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Functional Biomaterials is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

biomaterials
bone defect
sustained-release biomaterials
biomaterials for drug delivery
mRNA therapeutics
exosomes and extracellular vesicles
biomaterials for fracture repair

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Published Papers (10 papers)

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Research

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20 pages, 11676 KB

Open AccessArticle

Micro- and Nano-Structuring of Hydroxyapatite–MMT-Loaded Hydrogels for Bone Regeneration Applications

by Inbar Eshkol-Yogev, Tom Hanoon Kogan, Inbar Levi, Maya Salman, Ofir Gariani and Meital Zilberman

J. Funct. Biomater. 2026, 17(3), 121; https://doi.org/10.3390/jfb17030121 - 2 Mar 2026

Viewed by 729

Abstract

Bone regeneration focuses on the creation of functional tissue to repair bone defects. Creating a biodegradable scaffold hydrogel that combines a hemostatic agent with bioactive ceramics can afford the biological and mechanical benefits of both components. In the present study, we developed an injectable gelatin–alginate dual-composite hydrogel, loaded with two functional fillers: hydroxyapatite (HA) and the hemostatic agent montmorillonite (MMT). HA (microparticles and nanoparticles) was incorporated at concentrations of 10–30 mg/mL, with and without MMT at 20 mg/mL. The effects of functional fillers and their concentration on the microstructure and resulting physical and mechanical properties were studied, and a qualitative model summarising these effects was developed. All formulations exhibited clinically appropriate gelation times (5–29 s). n-HA significantly prolonged gelation time, reaching 29 ± 3 s at 30 mg/mL, while MMT reduced gelation time at all concentrations. The tensile strength of the unloaded hydrogel reached 20 kPa and increased to 57 kPa with 30 mg/mL of n-HA. The tensile strength even increased further with the addition of MMT (77 kPa). The results indicate that the combination of HA and MMT produced dual micro-composite hydrogels with moderate reinforcement, whereas the combination of n-HA and MMT generated dual nano–micro composites with combined reinforcing effects. The latter exhibited the highest strength and sealing ability while maintaining clinically relevant gelation times and controlled swelling behaviour. In conclusion, the combination of MMT with n-HA or HA enables the creation of functional hydrogels with controlled properties, tailored to specific applications in bone regeneration. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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15 pages, 6675 KB

Open AccessArticle

Biodistribution and Biodegradation of an Osteoinductive Supramolecular Polymer Implant in a Rat Spinal Fusion Model

by Jacqueline Inglis, Alyssa Goodwin, Steven Kurapaty, David M. Hiltzik, Rahim Laiwalla, Hogan Brecount, Nicholas A. Sather, Emily A. Waters, Chad R. Haney, Rebecca Sponenburg, Xinyi Lin, Wellington K. Hsu, Samuel I. Stupp, Erin L. Hsu and Romie F. Gibly

J. Funct. Biomater. 2026, 17(3), 107; https://doi.org/10.3390/jfb17030107 - 24 Feb 2026

Viewed by 743

Abstract

Recombinant human bone morphogenic protein-2 (rhBMP-2) use in spinal fusion is limited by dose-dependent complications. Peptide amphiphile (PA) supramolecular polymers presenting a BMP-2–binding epitope have previously been developed to reduce the rhBMP-2 dose required for successful fusion. We evaluated PA implant biodegradation and tissue clearance in a rat posterolateral spinal fusion model as a prerequisite to clinical safety studies. Twenty-three female Sprague–Dawley rats underwent L4–L5 fusion with gadolinium (Gd)-labeled PA implants. Longitudinal magnetic resonance imaging (MRI) was performed up to 13 weeks postoperatively, while the spine and filter organs were harvested for inductively coupled plasma mass spectrometry (ICP-MS) quantification of Gd at multiple time points. Gd concentration at the fusion site decreased from 71% of maximum to 19.5% at 13 weeks, and MRI showed a complete loss of Gd signal enhancement by 8 weeks. In peripheral organs, peak Gd accumulation was 3% in the liver at 4 weeks, declining to 1.4% at 13 weeks, while Gd remained below 0.05% in the spleen, lung, and blood at all time points. These data indicate PA implant localization, with robust degradation and clearance and minimal off-target accumulation, supporting its translational potential for spinal fusion applications. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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17 pages, 23065 KB

Open AccessArticle

The Influence of Ca on Mechanical Properties of the Mg–Ca–Zn–RE–Zr Alloy for Orthopedic Applications

by Mircea Cătălin Ivănescu, Corneliu Munteanu, Ramona Cimpoeșu, Bogdan Istrate, Fabian Cezar Lupu, Marcelin Benchea, Eusebiu Viorel Șindilar, Alexandru Vlasa, Ovidiu Stamatin and Georgeta Zegan

J. Funct. Biomater. 2025, 16(5), 170; https://doi.org/10.3390/jfb16050170 - 9 May 2025

Cited by 4 | Viewed by 1210

Abstract

Background: This study examined how the concentration of calcium (Ca) influences the microstructure, mechanical characteristics, and tribological attributes of Mg–Ca–Zn–RE–Zr alloys for orthopedic medicine. Materials and methods: Experimental alloys with 0.1 and 0.5 wt% Ca were prepared in a controlled atmosphere induction furnace. The microstructure of the alloys was investigated by scanning electron microscopy, the chemical composition by X-ray fluorescence and energy-dispersive spectroscopy, the mechanical properties by indentation and scratching, and the corrosion resistance by linear and cyclic potentiometry. Results: The alloy with 0.1% Ca exhibited greater fluctuations in the coefficient of friction, while the sample with 0.5% Ca showed a higher susceptibility to cracking. Regarding corrosion resistance, both samples exhibited a generalized corrosion trend with similar corrosion currents. At lower Ca concentrations (0.1%), the refined microstructure of the alloys provided an elastic modulus closer to that of human bone, minimizing the risk of excessive local stress and promoting uniform load distribution at the bone-implant interface. Conclusion: The 0.5% Ca alloy offered superior tribological stability and better shock absorption, making it suitable for applications requiring long-term stability. The study highlighted the potential of both compositions based on the specific requirements of biodegradable orthopedic implants. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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16 pages, 4410 KB

Open AccessArticle

Tomographic Assessment of Bone Regeneration in Osteochondral Lesion Treated with Various Biomaterials in a Sheep Model Study

by Taulant Goga, Bledar Goxha, Alberto Maria Crovace, Mario Cinone, Luca Lacitignola, Marta Guadalupi and Erinda Lika

J. Funct. Biomater. 2025, 16(4), 120; https://doi.org/10.3390/jfb16040120 - 1 Apr 2025

Viewed by 1501

Abstract

Osteochondral defects, involving both articular cartilage and subchondral bone, pose significant challenges to joint function and health due to the lack of spontaneous healing and the risk of long-term degenerative diseases like osteoarthritis. Biomaterials have emerged as important components in the development of scaffolds, providing structural support that facilitates tissue growth, integration, and regeneration. This study aims to demonstrate the effectiveness of a tomographic assessment method for optimizing the evaluation of osteochondral regeneration, particularly using Hounsfield units, to enable the evaluation of scaffold integration and tissue regeneration. The sheep model was selected as a model study. Two distinct configurations of biomaterials were utilized in this study: Honey (HMG—Mg doped hydroxyapatite; HWS—wollastonite–hydroxyapatite) and Bi-layer (BWS—wollastonite–hydroxyapatite). The HMG scaffold demonstrated superior integration, reparative tissue quality, and regeneration potential compared to the HWS, BWS, and CTRL groups. The findings underscore the significance of CT assessment as a preliminary method for evaluating hard tissue, such as bone, employing Hounsfield units. Statistical evaluations validated the significant differences in performance, particularly favoring the HMG group. The results of this study underscore the importance of tomographic assessment in evaluation of osteochondral regeneration. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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Review

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22 pages, 728 KB

Open AccessReview

Protein-Encoding Chemically Modified mRNAs for Musculoskeletal Tissue Regeneration and Repair

by Britney S. Force, Xueqin Gao and Johnny Huard

J. Funct. Biomater. 2026, 17(4), 167; https://doi.org/10.3390/jfb17040167 - 1 Apr 2026

Viewed by 686

Abstract

Musculoskeletal disorders and injuries are highly prevalent and encompass a broad range of conditions, including bone fractures and segmental defects, tendinopathies and tendon injury, and cartilage disorders such as osteoarthritis, cartilage defects, and intervertebral disc disease. These conditions can arise from diverse causes including trauma and injury, tumor resection, congenital abnormalities, and age-related degeneration. In the past decades, administration of chemically modified mRNA (cmRNA) encoding growth factors and transcriptional regulators has demonstrated effectiveness in repairing musculoskeletal tissues in preclinical studies. This review summarizes recent advancements in bone, tendon, cartilage, intervertebral disc, and muscle regeneration achieved through the localized delivery of protein-encoding mRNAs to express therapeutic target proteins. Delivery of cmRNA encoding growth factors such as BMP-2, BMP-9, VEGF, FGF-18, and IGF-1, or transcriptional regulators including Runx1, to various animal models has shown beneficial effects on bone, tendon, cartilage, and muscle injury repair in preclinical models. Alongside these progresses, the advantages and disadvantages of applying chemically modified mRNA for musculoskeletal tissue regeneration are also discussed. While studies show the promise of cmRNA for therapeutic applications in orthopedic tissue regeneration, more research is required to optimize growth factors and delivery methods, as well as validate long-term safety and efficacy prior to successful translation into new therapies to benefit patients. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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25 pages, 799 KB

Open AccessReview

Heparin-Based Biomaterials for Sustained Release of Growth Factors for Bone Tissue Engineering and Regeneration

by Keisuke Nakayama, Xueqin Gao, Britney S. Force, Marc J. Philippon and Johnny Huard

J. Funct. Biomater. 2026, 17(3), 156; https://doi.org/10.3390/jfb17030156 - 22 Mar 2026

Viewed by 909

Abstract

Large bone defects resulting from trauma, tumor resection, infection, or degenerative diseases pose a major clinical challenge in orthopedic surgery and regenerative medicine. Despite advances in biomaterials and surgical techniques, successful outcomes are often compromised by poor vascularization, limited osteoinduction, and donor-site morbidity associated with autografts or allografts. However, conventional delivery systems suffer from burst release, rapid clearance, off-target effects, and supraphysiologic dosing, which can lead to undesirable complications such as ectopic ossification and inflammation, with some reports raising concerns about the long-term tumorigenic risk. Heparin, a naturally highly sulfated glycosaminoglycan structurally related to heparan sulfate, has emerged as a particularly attractive candidate for affinity-based biomaterial systems. It naturally binds over 300 growth factors, including bone morphogenetic proteins. By protecting these proteins from enzymatic degradation, enhancing their bioavailability, and mediating receptor clustering, heparin provides both biochemical stability and biofunctional modulation. This review provides a comprehensive overview of heparin-based delivery strategies in bone tissue engineering. We begin by describing the biological functions of heparin in modulating growth factor activity. We then discuss in detail the different heparin-based biomaterials designed to sustain the release of growth factors for bone tissue engineering, including the heparin–polycation coacervate system; heparin-based supramolecules; and heparin-based hydrogels, nanoparticles, and microspheres for sustained release of bone morphogenic proteins and other growth factors for bone tissue engineering. Finally, we assess the clinical and translational relevance of heparin-based systems, identify key challenges, and outline future perspectives, highlighting the potential of these biomaterials for providing safer and more effective therapies for bone regeneration. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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22 pages, 378 KB

Open AccessReview

Three-Dimensional Printing of a Spinal Interbody: Design Principles, Biomaterials, and Translational Considerations

by Sahil Garg, Patrick Young, Christopher Franquemont, Rachel Conley and Sanjitpal Gill

J. Funct. Biomater. 2026, 17(3), 143; https://doi.org/10.3390/jfb17030143 - 12 Mar 2026

Viewed by 957

Abstract

Background: Interbody spinal fusion is a common surgical treatment for degenerative, traumatic, and deformity-related spinal pathologies. Despite advances in cage geometry and fixation strategies that improve alignment and early stability, reliable fusion remains limited by the mechanical and biological constraints of conventional interbody implant materials. Traditional titanium and polymer-based cages often fail to optimally balance load sharing, osteointegration, and biological activity within the mechanically demanding interbody environment. This narrative review examines the development and translational potential of 3D-printed interbody fusion devices, with emphasis on how additive manufacturing enables the integration of mechanical performance with biologically active scaffold design. Methods: A thorough literature review was performed to evaluate the evolution, design principles, material properties, and translational outcomes of three-dimensional (3D)-printed interbody fusion devices. Results: Additive manufacturing enables precise control over implant architecture, allowing for the fabrication of porous, lattice-based cages with tunable stiffness, optimized load sharing, and enhanced bone–implant integration. Preclinical and early clinical studies suggest that 3D-printed porous titanium cages may reduce subsidence, promote osteointegration, and improve fusion-related outcomes compared with conventional designs. Emerging evidence indicates that scaffold porosity, surface microtopography, and bioactive coatings influence macrophage polarization, angiogenesis, and osteogenic signaling. Polymeric and composite constructs, particularly hybrid designs incorporating surface functionalization, represent promising adjuncts, though clinical evidence remains limited. Conclusions: Three-dimensional printing represents a paradigm shift in interbody fusion device design. Continued translational research and longer-term clinical follow-up are required to validate efficacy and guide widespread clinical adoption. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

28 pages, 3174 KB

Open AccessReview

Advanced Biomaterial-Based In Vitro Osteoarthritis Models: Integrating Sex as a Biological Variable in Hormonal, Subchondral Bone, and Mechanobiological Pathways

by Elisa Capuana, Angela De Luca, Viviana Costa, Lavinia Raimondi, Daniele Bellavia, Valerio Brucato, Gianluca Giavaresi and Vincenzo La Carrubba

J. Funct. Biomater. 2026, 17(1), 35; https://doi.org/10.3390/jfb17010035 - 10 Jan 2026

Viewed by 1149

Abstract

Osteoarthritis (OA) is the most common form of arthritis and represents a major clinical and socioeconomic burden. Epidemiological data consistently show that OA affects women more frequently and, in several joints, more severely than men. Nevertheless, current in vitro models rarely consider sex-specific variables, limiting their ability to capture the biological mechanisms that shape the pathogenesis and progression of OA. Increasing evidence indicates that age-related hormonal fluctuations and subchondral bone remodeling strongly influence OA evolution, and that these processes differ between the sexes. For instance, the decline in estrogen levels during menopause has been associated with accelerated cartilage degeneration, increased osteoclastic activity, and a higher susceptibility to subchondral bone alterations, which may contribute to more aggressive clinical manifestations in women. These mechanisms are only partially reproduced in widely used experimental systems, including traditional biomaterial scaffolds and simplified osteochondral constructs, leaving important sex-dependent pathways unresolved. While advanced biomaterials enable precise control of stiffness, porosity, and biochemical cues, most current in vitro OA models still rely on sex-neutral design assumptions, limiting their ability to reproduce the divergent disease trajectories observed in men and women. By integrating material properties with dynamic loading and tunable hormonal conditions, next-generation in vitro systems could improve mechanistic understanding, increase the reliability of drug screening, and better support the development of sex-specific therapies through the combined efforts of bioengineering, materials science, cell biology, and translational medicine. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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15 pages, 602 KB

Open AccessReview

Advances in Synthetic Polymer Membranes for Guided Bone Regeneration in Dental Implants: A Scoping Review

by Belén Lima-Sánchez, María Baus-Domínguez, María-Angeles Serrera-Figallo and Daniel Torres-Lagares

J. Funct. Biomater. 2025, 16(5), 149; https://doi.org/10.3390/jfb16050149 - 22 Apr 2025

Cited by 10 | Viewed by 5399

Abstract

Background: Different approaches are proposed for bone volume gain in the case of atrophic alveolar ridges, with guided bone regeneration (GBR) and guided tissue regeneration (GTR) being the most used techniques. These techniques require the placement of barrier membranes, which is the main element of the bone growth strategy, among which there is a wide range depending on their origin or degradation. This literature review aims to provide an update on the latest advances in polymeric membranes of synthetic origin currently used in bone regeneration. Materials and Methods: Two bibliographic searches were carried out in the PubMed (MEDLINE) and Scopus databases using a search strategy in which inclusion and exclusion criteria were applied. Results: For the selection of articles, the PRISMA guide flow chart was followed, and after a selection process, 11 articles were analyzed based on the characteristics of the marketed membranes and the results obtained after their use. Conclusions: It can be concluded that polymeric membranes play a fundamental role in guided bone regeneration, providing an effective barrier that facilitates bone growth and improves the success of dental implantology treatments. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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Other

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17 pages, 1391 KB

Open AccessSystematic Review

Autologous and Heterologous Minor and Major Bone Regeneration with Platelet-Derived Growth Factors

by Gianna Dipalma, Angelo Michele Inchingolo, Valeria Colonna, Pierluigi Marotti, Claudio Carone, Laura Ferrante, Francesco Inchingolo, Andrea Palermo and Alessio Danilo Inchingolo

J. Funct. Biomater. 2025, 16(1), 16; https://doi.org/10.3390/jfb16010016 - 9 Jan 2025

Cited by 9 | Viewed by 2278

Abstract

Aim: This review aims to explore the clinical applications, biological mechanisms, and potential benefits of concentrated growth factors (CGFs), autologous materials, and xenografts in bone regeneration, particularly in dental treatments such as alveolar ridge preservation, mandibular osteonecrosis, and peri-implantitis. Materials and Methods. A systematic literature search was conducted using databases like PubMed, Scopus, and Web of Science, with keywords such as “bone regeneration” and “CGF” from 2014 to 2024. Only English-language clinical studies involving human subjects were included. A total of 10 studies were selected for qualitative analysis. Data were processed through multiple stages, including title and abstract screening and full-text evaluation. Conclusion: The findings of the reviewed studies underscore the potential of the CGF in enhancing bone regeneration through stimulating cell proliferation, angiogenesis, and extracellular matrix mineralization. Autologous materials have also demonstrated promising results due to their biocompatibility and capacity for seamless integration with natural bone tissue. When combined with xenografts, these materials show synergistic effects in improving bone quantity and quality, which are crucial for dental implant success. Future research should focus on direct comparisons of different techniques, the optimization of protocols, and broader applications beyond dental medicine. The integration of CGFs and autologous materials into routine clinical practice represents a significant advancement in regenerative dental medicine, with the potential for improved patient outcomes and satisfaction. Full article

(This article belongs to the Special Issue Advanced Biomaterials for Bone Tissue Engineering)

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