Novel 3D-printed Synthetic Scaffolds Offer Personalized Repair of Major Bone Injuries

Spotlight: Novel 3D-printed Synthetic Scaffolds Offer Personalized Repair of Major Bone Injuries

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By: Hala Zreiqat, Ph.D.

Figure 1: X-ray image of an Sr-HT Gahnite scaffold in a rabbit segmental bone defect (arrows) for 12 weeks, achieving complete defect bridging.

Figure 1: X-ray image of an Sr-HT Gahnite scaffold in a rabbit segmental bone defect (arrows) for 12 weeks, achieving complete defect bridging.

The majority of traumatic injuries sustained during combat involve the extremities (limbs, hands, and feet), and around one-quarter of these involve damage to the bone [1,2]. In recent years, the medical challenge of repairing such damage has increased due to the growing incidence of blast trauma caused by improvised explosive devices and roadside bombs. These injuries typically involve the lower extremities and tend to be extensive and complex; they require major surgical intervention, often amputation [3].

Although therapeutic options for many orthopaedic injuries have improved considerably over the years, the repair of extensive bone damage, especially where bones are under load (e.g., femur, tibia, vertebral body), has proved an intractable problem [4,5]. Recently, however, researchers at the University of Sydney in Australia have developed synthetic bone materials that seek to overcome this long-standing challenge.

Synthetic materials have become a high-demand alternative to bone grafts. The “gold standard” autograft, which is typically harvested from the patient’s iliac crest (part of the pelvis), is associated with a high (20 percent average) risk of morbidity, including deep infection, major haematoma, iliac fracture, nerve injury, pelvic instability, and chronic pain at the donor site [5,6,7]. The alternative is an allograft from a bone bank—often required for large defects, when autograft bone is insufficient—but allografts are limited in supply and plagued by variable bioactivity and the risks of immune rejection and disease transmission. For these reasons, a wide range of synthetic bone materials has been developed over the past 30 years. Yet nothing suitable for the repair of large bone defects under load has made the transition from laboratory to clinic [8,9].

A major challenge is the inverse relation between strength and bioactivity. Strength is required to withstand load. Bioactivity is required to induce the growth of new bone. Strength demands a less porous material, bioactivity a more. Currently the stronger synthetics lack adequate bioactivity, and the more bioactive ones lack adequate strength

University of Sydney researchers have addressed this problem with two novel (patented) calcium-silicate-based bioceramics: Sr-HT Gahnite (Sr-Ca2ZnSi2O7) and Baghdadite (Ca3ZrSi2O9). These materials have been developed using a combination of strategies: composite (multi-phase) structure to increase strength; novel chemical composition incorporating osteogenic ions to induce bone growth; computational modelling of internal architecture (e.g., pore size, interconnectivity, strut geometry) to produce the optimal balance between strength and bioactivity; and a new fabrication process to address shortcomings of the conventional (polymer sponge) method.

Using 3-D printing technology, the materials can be fabricated into strong yet highly porous scaffolds of any shape or size. And by optimizing this technology, researchers have established tight control over the materials’ internal architecture— for example, enabling the strength to bioactivity ratio to be subtly adjusted depending on patient need.

The preclinical results for both materials are promising. Baghdadite scaffolds implanted into large bone defects in sheep tibiae for 26 weeks withstood the physiological loads and induced substantial bone formation without supplementation by cells or growth factors. Notably, all samples showed significant (80 percent average) bridging of the defect by new bone, with evidence of bone infiltration and remodelling within the scaffold implant.

Sr-HT Gahnite scaffolds implanted into critical-sized defects in rabbit radii induced extensive new bone formation, with complete bridging of the defect at 12 weeks and clear evidence that the original radial architecture and bone marrow environment were regenerating (see Figure 1). The TCP/HA controls (tricalcium phosphate/hydroxyapatite scaffolds currently used in the clinic) exhibited only partial bridging. The Sr-HT Gahnite scaffolds also demonstrated greater structural integrity than the TCP/HA controls. Indeed, they achieved a compressive strength comparable to that of bone and considerably higher than that reported for glass, ceramic, and glass-ceramic constructs with similar porosity and interconnectivity. Additional preclinical results and ongoing experiments are confidential. But even the results reported here are significant achievements not realized by other synthetic scaffolds currently available or under development.

Sr-HT Gahnite and Baghdadite possess another advantage: they are bioresorbable. Over time, as native bone grows back through the scaffold, the scaffold itself is slowly absorbed into the body, leaving no permanent remains that may lead to infection or rejection. There are other bioresorbable materials on the market, but they are weak in compressive and tensile strength and so are restricted to fillers (in granule form) and nonload-bearing situations. In contrast, strong materials, such as PEEK and titanium, are permanent fixtures that lack bioactivity.

This bioceramic bone material simultaneously offers bioactivity, strength, and resorbability. Interestingly, it may offer an additional feature. In vitro studies have shown bioceramics deter bacteria from adhering to the scaffold. If these inherent antibacterial properties are confirmed in vivo, it would mean that a common complication of bone grafting, in which bacterial biofilms cling to the graft and cause infection, could simultaneously be minimized. These new bioceramics are now under global licence to product development companies in Germany (Baghdadite) and Australia (Sr-HT Gahnite).

These synthetic bone materials could be of immense benefit in treating combat-related injuries. During Operation Iraqi Freedom and Operation Enduring Freedom (Afghanistan), some 54 percent of reported combat wounds were extremity injuries (75 percent of these injuries due to explosive munitions), with 48 percent of the consequent lower extremity injuries being fractures of the tibia and fibula [1].

In the Afghanistan counterinsurgency military operations from 2010 onward, most casualties resulted from dismounted complex blast injuries—severe injuries from explosive devices incurred while personnel are on foot patrol [10]. Civilians are also afflicted by suicide bombs, vehicle bombs, and mortars [11], and even when peace has resumed, unexploded ordnance, such as landmines, continue to cause major injuries [12,13]. As these synthetic materials can be 3-D printed on-site, this alleviates the need to perform orthopaedic surgical procedures near bone banks, which are not always readily available in austere environments.

These bioceramics can be used to promote tissue growth earlier, which is beneficial because of the nonlethal polytraumatic wounds often experienced in combat. For example, these synthetic materials can be used in maxillofacial reconstruction, long bone fractures, repair of non-union fracture, and spinal fusion. Additional non-combat-related conditions may also be treated with these materials, such as osteoporosis and bone removal due to cancer, which may be relevant to aging veterans.

More than 2 million bone grafting procedures are performed worldwide each year, with half a million performed in the U.S. alone [14], and the global market for bone graft substitutes is expected to reach $3.2 billion by 2022 [15]. Therefore, exponential growth in the research and development related to tissue and bone regeneration and the technologies associated with them (e.g., 3-D printing and synthetic biology) is expected to continue.

References

  1. Owens, B. D., Kragh, J. F., Macaitis, J., Svoboda, S. J., & Wenke, J. C. (2007). Characterization of extremity wounds in Operation Iraqi Freedom and Operation Enduring Freedom. Journal of Orthopaedic Trauma, 21(4), 254-257. doi:10.1097/bot.0b013e31802f78fb
  2. Kragh, J. F., Kirby, J. M., & Ficke, J. R. (2012). Extremity injury. In Combat Casualty Care: Lessons Learned from OEF and OIF (pp. 393-484). Office of the Surgeon General, Department of the Army, United States of America.
  3. Pasquina, P. F., Emba, C. G., Corcoran, M., Miller, M. E., & Cooper, R. A. (2017). Lower limb disability: Present military and civilian needs. In Full Stride: Advancing the State of the Art in Lower Extremity Gait Systems (pp. 17-33). New York, NY: Springer-Verlag.
  4. Redman, S., Oldfield, S., & Archer, C. (2005). Current strategies for articular cartilage repair. European Cells and Materials, 9, 23-32. doi:10.22203/ecm. v009a04
  5. Seiler, J. G., III, & Johnson, J. (2000). Iliac crest autogenous bone grafting: Donor site complications. Journal of the Southern Orthopaedic Association, 9(2), 91-97.
  6. Dimitriou, R., Mataliotakis, G. I., Angoules, A. G., Kanakaris, N. K., & Giannoudis, P. V. (2011). Complications following autologous bone graft harvesting from the iliac crest and using the RIA: A systematic review. Injury, 42. doi:10.1016/j.injury.2011.06.015
  7. Oakley, M. J., Smith, W. R., Morgan, S. J., Ziran, N. M., & Ziran, B. H. (2007). Repetitive posterior iliac crest autograft harvest resulting in an unstable pelvic fracture and infected non-union: Case report and review of the literature. Patient Safety in Surgery, 1(1), 6. doi:10.1186/1754-9493-1-6
  8. Pilia, M., Guda, T., & Appleford, M. (2013). Development of composite scaffolds for load-bearing segmental bone defects. BioMed Research International, 2013, 1-15. doi:10.1155/2013/458253
  9. Dong, W., Hou, L., Li, T., Gong, Z., Huang, H., Wang, G., . . . Li, X. (2015). A dual role of graphene oxide sheet deposition on titanate nanowire scaffolds for osteo-implantation: Mechanical hardener and surface activity regulator. Scientific Reports, 5(1). doi:10.1038/srep18266
  10. Eastridge, B. J., Mabry, R. L., Seguin, P., Cantrell, J., Tops, T., Uribe, P., . . . Blackbourne, L. H. (2012). Death on the battlefield (2001–2011). Journal of Trauma and Acute Care Surgery, 73. doi:10.1097/ta.0b013e3182755dcc
  11. Hicks, M. H., Dardagan, H., Serdán, G. G., Bagnall, P. M., Sloboda, J. A., & Spagat, M. (2011). Violent deaths of Iraqi civilians, 2003-2008: Analysis by perpetrator, weapon, time, and location. PLoS Medicine, 8(2). doi:10.1371/ journal.pmed.1000415
  12. Soroush, A. R., Flahati, F., Zargar, M., Soroush, M. R., Khateri, S., & Khaji, A. (2010). Women pose innocent victims of landmines in postwar Iran. Iranian Journal of Public Health, 39(1), 32-35.
  13. Bilukha, O. O. (2005). Injuries and deaths caused by unexploded ordnance in Afghanistan: Review of surveillance data, 1997-2002. The BMJ, 330(7483), 127-128. doi:10.1136/bmj.38337.361782.82
  14. Campana, V., Milano, G., Pagano, E., Barba, M., Cicione, C., Salonna, G., . . . Logroscino, G. (2014). Bone substitutes in orthopaedic surgery: From basic science to clinical practice. Journal of Materials Science: Materials in Medicine, 25(10), 2445-2461. doi:10.1007/s10856-014-5240-2
  15. Global Industry Analysts, Inc. (2016, April). Bone graft substitutes: A global strategic business report. Retrieved from http://www.strategyr.com/MarketResearch/infographTemplate.asp?code=MCP-1637

 

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