Written by Jamie Saito ‘25
Edited by Surya Khatri '24
With an aging population, a higher prevalence of obesity, and a decrease in physical activities, the risk of bone disorders has increased, resulting in a higher incidence of bone defects. Though bone tissue possesses a regenerative capacity, cracks and fractures that exceed two centimeters are considered critical defects [1]. Without clinical intervention, these disorders will result in weakness and scar formation.
Current surgical techniques largely rely on two techniques: grafting and synthetic substitutes. Grafting consists of two subcategories, autografts and allografts. While both refer to transplanted bone tissue, autografts refer to bone tissue from another site within the body while allografts refer to tissue from another donor. However, this is linked to an increased risk of infection or disease transmission, which may be particularly detrimental for older patients [2]. Synthetic substitutes, such as metal fixation devices, usually require subsequent surgical interventions [3]. Because of these limitations, finding alternative techniques to treat affected patients is important.
Bone tissue engineering aims to promote the natural regenerative properties of bone at the site of defect, allowing new tissue to fill in the cracks or fractures in the native tissue. Ultimately, a successfully engineered system will be able to “carry loads, regrow, and repair damaged bone tissues beyond the natural healing capacity of the human body” [4]. To do so, scientists use a scaffold structure to act as a backbone for new bone tissue. This structure can act as an extracellular matrix, providing mechanical support on which cells can begin to attach. Cells can either be included in the scaffolded structure, or they can be recruited from the native tissue [3]. However, including biological materials like cells in these designs increases cost and complexity because they must be cultured sterilly, which takes time and resources. Instead, materials can be “designed to interact with local tissues and cells to alter the normal healing process” [5]. Bone-tissue engineering can thus focus on optimizing material choices so that cells are recruited from native tissue to regenerate bone.
Material Selection Criteria
Before choosing these materials, engineers must consider the design constraints of the scaffolded structure. The most important constraint is biocompatibility. This means that the material should be able to function as planned in the human body without causing harm to the health of the patient.
As cells begin to populate the scaffold, they will begin creating their own extracellular matrix, making the continued presence of a synthetic structure unnecessary. It is therefore important that the scaffold degrades at the same rate that mineralization of bone occurs, allowing new tissue to completely replace the implanted structure [3]. This requires careful selection of mechanical and chemical properties. The decomposition of synthetic materials should not result in harmful effects to the human body, such as altering the pH or releasing toxic materials into the body.
It is important to consider not only the biocompatibility of possible materials, but also the mechanical features of bone tissue while designing an artificial scaffold. Bone serves as structural support in the body and thus the materials must be able to withstand the mechanical loading that occurs under normal physiological conditions. The materials must have similar strength and elastic properties as natural bone. For example, while standing, there is a large amount of compressive force placed on the bones throughout the body due to gravity, so choosing a material that is able to withstand these forces is integral in ensuring that the scaffold will be able to function at the same level as normal tissue. However, these mechanical properties should match those of bone as closely as possible to prevent additional negative effects, such as stress shielding. Stress shielding occurs if a material is significantly stronger than native tissue, causing it to experience more loading than the natural bone. This leads to a decrease in bone density around the implant and weakens healthy tissue [3].
Beyond these mechanical properties, it is also important that the new tissue is able to receive adequate oxygen and nutrients to grow. Bone-tissue engineering must ensure that the scaffolded structure will support the presence of blood vessels. Vascularization is critical to provide the new tissue with necessary nutrients and oxygen, allowing it to mature and integrate with the body. Materials should therefore have pores with a diameter of 100-300 micrometers to support vascularization and innervation [3]. This will promote integration of newly regenerated tissue into the body and ensure the tissue-engineered product functions as well as native bone.
Material Solutions
Ceramics, metals, and polymers are considered primary candidates for this application. However, it is unlikely that one material will be able to solely mimic the properties of bone. Biocompatible ceramics are one of the most popular choices for current bone tissue engineering scaffolds because they share similar composition to bone. However, they are more brittle and thus fracture more easily [6]. Biodegradable metals are another option because they are mechanically very strong. However, they are not as elastic as natural tissue and may thus lead to a stress shielding phenomenon, where load is only applied to implant thus weakening nearby tissue [3,6]. Polymers have a wide range of mechanical properties and may be designed to be reabsorbed into the body. However, they are not as strong as ceramics and metals [6].
Because of these limitations, the best solution may be to design a multilayered composite material. By combining ceramics, metals, and polymers, scientists can harness ideal properties from each, creating a stronger material that more closely resembles bone. One iteration of this design is the synthesis of ceramics and polymers. Since ceramics have similar structure and strength as bone, a polymer component may be added to decrease the brittleness of the material. Recent research has focused on this form of composite material, providing promising results.
A paper published in 2017 studied the effect of a synthetic polymer and ceramic composite material. Researchers used Polycaprolactone (PCL), a nontoxic and bioabsorbable polymer, and hydroxyapatite (HA), a sodium phosphate bioceramic, which are popular materials being studied for bone tissue scaffold applications. They studied whether this material could promote the repair of articular cartilage and underlying bone. They implanted the material into an area of bone defect in a rabbit model After 12 weeks, the composite material had promoted bone formation, resulting in increased bone volume and bone mineral density [7]. These results illustrate that the composite polymer-ceramic material is a promising choice to promote bone regeneration.
Another study in 2016 further demonstrated that a ceramic and polymer composite material would not only promote regeneration of tissue but also prevent a negative immune response to the material. Jakus et al. 3-D printed hyperelastic “bone” consisting of a ceramic and polymer composite. They found that these materials did not trigger an immune response, which addresses concerns that synthetic materials may lead to toxic immune responses in the body. In a research primate model, the hyperelastic “bone” integrated into native tissue within four weeks with evidence of vascularization [8]. These in vivo results provide promising evidence that careful material selection can create the next generation of bone tissue engineering.
Conclusion
With bone disorders becoming an increased concern for the orthopedic field, bone tissue engineering may provide the medical community with a putative solution. This approach aims to harness the naturally regenerative properties of bone to repair cracks. By selecting materials that align with both the mechanical and biological constraints of bone, scientists can then design scaffolds that can be implanted into these areas of weakness and promote the recruitment of nearby cells to create new, healthy tissue. Furthermore, because grafting techniques currently require subsequent surgeries to remove the synthetic scaffolds, designing a structure that can safely degrade within the body will prevent multiple interventions. Though complex, the refinement of bone tissue engineering holds a promising future for more effective orthopedic healthcare.
References
1. Schemitsch EH. Size Matters: Defining Critical in Bone Defect Size! J Orthop Trauma. 2017 Oct;31:S20.
2. Recent approaches towards bone tissue engineering | Elsevier Enhanced Reader [Internet]. [cited 2022 Nov 27]. Available from: https://reader.elsevier.com/reader/sd/pii/S8756328221004221?token=8C22E7FBCE58EFEB779F47BFFA314D0D11E7C128D471BBFCBE5F9F2476F47F2726A726A674BBC982EF3D2F550CA0AA4C&originRegion=us-east-1&originCreation=20221127234245
3. Koons GL, Diba M, Mikos AG. Materials design for bone-tissue engineering. Nat Rev Mater. 2020 Aug;5(8):584–603.
4. Al-Barqawi MO, Church B, Thevamaran M, Thoma DJ, Rahman A. Design and Validation of Additively Manufactured Metallic Cellular Scaffold Structures for Bone Tissue Engineering. Materials. 2022 Jan;15(9):3310.
5. Burdick JA, Mauck RL, Gorman JH, Gorman RC. Acellular Biomaterials: An Evolving Alternative to Cell-Based Therapies. Sci Transl Med. 2013 Mar 13;5(176):176ps4.
6. Ghassemi T, Shahroodi A, Ebrahimzadeh MH, Mousavian A, Movaffagh J, Moradi A. Current Concepts in Scaffolding for Bone Tissue Engineering. Arch Bone Jt Surg. 2018 Mar;6(2):90–9.
7. Du Y, Liu H, Yang Q, Wang S, Wang J, Ma J, et al. Selective Laser Sintering Scaffold with Hierarchical Architecture and Gradient Composition for Osteochondral Repair in Rabbits. Biomaterials. 2017 Aug;137:37–48.
8. Jakus AE, Rutz AL, Jordan SW, Kannan A, Mitchell SM, Yun C, et al. Hyperelastic “bone”: A highly versatile, growth factor–free, osteoregenerative, scalable, and surgically friendly biomaterial. Sci Transl Med. 2016 Sep 28;8(358):358ra127-358ra127.
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