Inspired by Nature: New Implants for Bone Repair

The human skeleton is absolutely remarkable: it acts as a mobile scaffold that protects soft tissues and organs, stores minerals, and produces blood and immune cells. The 206 bones that make up the adult human skeleton are also notable for their extraordinary ability to heal and self-repair after damage. This is due to the remarkably flexible nature of bones, which serve as a framework for the minerals that together form a strong and solid skeleton. Bone healing after fracture begins within a few hours of the injury. Because there is bleeding, the body attempts to defend the injured region by forming a protective blood clot, which promotes inflammation at the fracture site (Loi et al., 2016). This provides the structural basis for the development of new bone. Bone growth starts when blood clots caused by inflammation are replaced by cartilage and fibrous tissue, often referred to as soft callus. The soft callus is replaced by hard bone (also known as hard callus) as the fracture heals, a role filled by osteoblast cells, which form new bone and add minerals to harden it. Newly synthesized strands of bone move towards each other until the fracture closes and the callus is absorbed. Eventually, osteoclasts tear away additional bone around the fracture until it fully heals and returns to its original shape (Remedios, 1999).

However, certain fractures and deformities require therapeutic intervention for proper alignment and healing. In such cases, fractured bones require the support of what is called an implant, an artificial device designed to replace or support a missing part of the human body. In the event of a bone injury, an implant is designed to help the bone return to its normal function as it was before the injury. As with any implant, the material used to manufacture the implants must be carefully considered. If the wrong material is used, bone fractures, deformities or incomplete bone healing can occur (Wiesel & Delahay, 2007). The introduction of a foreign object into the body can indeed lead to a range of complications, including infections. While numerous processes and materials are being investigated to improve bone implants, these are frequently connected to difficult-to-treat bacterial infections, particularly bone-repair implants. Infection after fracture fixation is a feared complication in orthopedic surgery that can result in non-union, loss of function, and even amputation. In addition to being a major cause of morbidity and mortality, it also imposes a significant socio-economic hardship (Hak et al., 2014).

Figure 1 - Bone x-rays aid doctors in evaluating fractures, injuries, and joint abnormalities (Rogers, 2018).

The Inside of a Bone: A Life of Building, Rebuilding, and Repairing

In the event of an injury, bone has the capacity to self-regenerate and recover its biological and mechanical properties before irreparable damage occurs. Bone is a dynamic tissue that continually undergoes change (Giannoudis et al., 2007; Wiesel & Delahay, 2007). This is due to the inner structure of bones, which consists of living cells interspersed with a bone matrix consisting of fibers and minerals that form a structural framework between cells. Calcium and phosphorus combine to form the mineral hydroxyapatite, which contributes to bones’ growth and hardening. The compressive strength and resistance to breaking of bones is guaranteed by such minerals which constitute 65-70% of their mass. Collagen, a natural fiber that strengthens bone tissue and increases its elasticity, makes up most of the remaining 30–35% of bone (Oryan et al., 2015). The tensile strength of the skeleton, i.e., the resistance to fracture under tension or compression, is provided by fibers that ensure bones don’t break when pulled. Bones include four primary types of specialized bone cells. Osteogenic cells, a type of stem cell, are the only bone cells that can proliferate and are essential as they produce all other types of bone cells. Osteoblasts, which are in charge of bone formation, strengthen bones by assembling a protein-based matrix on which hydroxyapatite builds up. These cells are at the heart of bone’s ability to self-repair during fracture healing, a process known as regeneration. Osteocytes are responsible for the maintenance and formation of new bones, as well as communicating with other cells and coordinating the actions of osteoblasts and osteoclasts during bone formation. Osteoclasts serve thereby as bone housekeeping workers, i.e., if a bone needs repairing, they are responsible for removing the old bone (Mohamed, 2008).

Orthopedic Implants: When the Bone Fails to Self-Repair

Fractures are breaks or cracks in a bone that develop when the force applied on it is greater than the bone's structural capacity, and they are the most common large-organ, traumatic injuries in humans. Because broken bones heal on their own, the goal of medical therapy is to ensure that the fragments of bone are properly lined up, and treatment involves immobilizing the bone with a plaster cast so that the bone may gradually regenerate. Orthopedic implants, on the other hand, are required for severe fractures that require realignment and fixation for proper healing, or when bone fails to regenerate entirely, resulting in bone abnormalities. These implants perform joint or bone functions in the human body and include hip and knee replacements, plates, pins, rods and screws (Wang et al., 2011). These implants must be designed taking into account the biocompatibility and mechanical properties of the material, so that the implant closely resembles the mechanical properties of bone, integrates with the surrounding tissue and preserves its integrity (Kim et al., 2020). Interestingly, while fractures and defects may be the underlying reason for the need for an implant, they may be also caused by the implant itself. Noteworthy, bone is the most transplanted tissue in the human body after blood (Faour et al., 2011; Turnbull et al., 2018). In order to effectively treat damage to the skeletal system without endangering the patient, orthopedic devices must be carefully designed. Metals, polymers and ceramics have been used as orthopedic biomaterials, although metals offer the most desirable properties (Ratner et al., 2004).

Figure 2 - An orthopedic implant is a medical device designed to replace a bone, joint, or cartilage due to damage or deformity (Brody, 2021).

The implants used for internal fixation are often constructed of stainless steel or titanium, which are both durable and robust, and commonly consist of metal rods or plates that hold the bone fragments together. These implants can also be manufactured of cobalt and chrome if a joint has to be replaced rather than repaired (Hayes & Richards, 2010; Marti, 2000). However, introducing foreign objects into the body poses potential risks that can lead to various health complications, including prolonged hospitalization, long-term antibiotic therapy, bacterial resistance and the development of superbugs, revision surgery (a surgery performed to correct or replace a failed implant), or even death. The surgical treatment of skeletal fractures can be very complex due to the unpredictability of bone damage, the multitude of concomitant injuries to be considered and the frequency of life-threatening situations in emergency care. Infection after fracture fixation is one of the most feared and challenging consequences in the management of patients with musculoskeletal trauma, as it can delay healing, result in permanent loss of function, or even amputation of the affected limb. Because of this, the topic of implant-related bone infections has gained increasing traction in the clinical and preclinical arenas during the last few decades (Metsemakers et al., 2018).

Implant Infections: A Safe Haven for Opportunistic Bacteria

The surgical placement of implants and other medical devices has become commonplace and is often life-saving. Globally, the number of total hip replacements is anticipated to be about one million per year, with knee replacements reaching 250,000 (Schierholz & Beuth, 2001). However, implant insertion in the body, particularly for the repair of exposed fractured bones and joint revision surgeries (where an old joint is removed and replaced with a new one), increases the risk of infection (Duan & Wang, 2006). The most prevalent type of life, bacteria, are found virtually anywhere on the globe. Infectious bacteria can be found around operating rooms, in surgical instruments, in medical staff and their clothing, or on the skin and body of the patient (Chevalier & Gremillard, 2009). Despite several advancements in biomaterials, a sizable fraction of implants are colonized by bacteria and serve as a starting point for implant-associated infections (Anderson et al., 1996). Up to two-thirds of all bacteria involved in orthopedic implant infections are Staphylococcus, which are the main culprits of two types of bone infection of particular concern: osteomyelitis and septic arthritis, both of which induce inflammatory destruction of bones and joints (Ribeiro et al., 2012).

Figure 3 - A feared complication in orthopedic surgery is infection after fracture fixation, which can lead to suboptimal bone repair and loss of function (Donohue, 2015).

Orthopedic implant failure is primarily a result of infection. These infections are challenging to treat and may require the replacement of the implant or even limb amputation (Ercan et al., 2011). Implant-associated infections are caused by bacterial adherence to the implant surface and subsequent biofilm formation at the implantation site (Zilberman & Elsner, 2008). Biofilms consist of clusters of bacteria that are either attached to a surface or to each other and embedded in a self-produced polysaccharide matrix. Host defenses typically fall short of preventing surface colonization of biofilm-forming bacterial strains. Thus, limiting bacterial adhesion is essential for preventing infections since biofilms are extremely resistant to the immune system and antibiotics (Davies, 2003; Gristina et al., 1988). As a result, for orthopedic implants to be effective, implant materials must be biocompatible with bone-forming cells (favoring osteoblast adhesion), inhibit the formation of soft connective tissue (preventing fibroblast adhesion), and prevent bacterial adhesion (Montanaro et al., 2008). The growth of biofilms on medical equipment poses three notable issues: First and foremost, the bacterial populations that live on such surfaces can spread throughout the body and produce a persistent infection; second, these bacterial communities are extremely challenging to eliminate with typical antimicrobial medications; finally, because host defenses and antimicrobial therapies fail to remove the biofilm, a chronic inflammatory response may manifest at the location of the biofilm (Nazhat et al., 2009). The emergence of microorganisms that are resistant to antibiotics and the modern world's antibiotic resistance crisis has further heightened these concerns.

Inspired by Nature: Insect Wings for Improved Medical Implants

Orthopedic implants have been a staple of the medical sector, and the prospect of increasing demand for implants calls for a decline in failure rates, particularly those caused by bacterial infections. Antibiotics and antibacterial coatings have been developed over the past two decades to reduce the need for revision surgery and infection-related deaths. However, due to the ineffectiveness of such approaches, scientists are now looking at nano-textured surfaces, i.e., surfaces which are covered with nano-sized structures, that resemble the bactericidal traits of many animal, plant, and insect species. Natural surfaces provide continuing and growing sources of inspiration and motivation for researchers to replicate their antibacterial properties in the quest for strategies to protect implants against infection (Ivanova et al., 2012). For many years, the medical industry has benefited tremendously from biomimicry, the process of designing objects inspired by observations of the natural world. Natural surfaces, such as lotus leaves, taro leaves, and shark skin, have the capacity to prevent bacterial adhesion due to the presence of surface patterns and micro- and nano-structures, a feature known as anti-biofouling surface. On the other hand, surfaces that are bactericidal, such as the skin of geckos and the wings of dragonflies and cicada, disrupt and destroy bacteria.

Figure 4 - Cicada's wings have inspired scientists to design improved medical implants (Kuper, 2021).

Due to their nanoscale pillar structure, the wings of cicada and dragonfly species have bactericidal effects on some bacterial strains (Bandara et al., 2017; Pogodin et al., 2013). As an outcome of the identification of these structures and the numerous applications that follow from them, a considerable amount of research is currently being done to replicate the structure of these naturally existent surfaces in order to mimic their behavior. Rather than using chemical methods to eliminate bacteria, researchers have focused on strategies to eradicate them by altering the physical topology of material surfaces. The fact that bacterial cell walls have been shown to enlarge and deform upon contact with textured surfaces forms the basis of this search (Hasan et al., 2013; Pogodin et al., 2013). Since nanotextured surfaces greatly enhance the contact adhesion area, they produce more potent bactericidal effects than flat surfaces, rendering them extremely advantageous. Because of its distinctive wings with antibacterial properties, the cicada species has lately caught the interest of experts. The whole surface of the cicada's wings is covered by extremely small pillars that measure in the billionths of a meter range (called nanometer pillars or nanopillars) (Ivanova et al., 2012; Tobin et al., 2013). Particularly noteworthy is the discovery by Ivanova et al. (2012) that P. aeruginosa cells are destroyed by cicada wings 3 minutes after contact. Cicada wings act as efficient antibacterial surfaces as opposed to anti-biofouling surfaces, with bacteria being pierced by the nanopillar arrays on the wing surface, resulting in bacterial cell death.

When nature meets science, the first challenge scientists encounter when creating implants for bone regeneration is biocompatibility, which means the material must not be hazardous to the host nor induce immunological rejection. Titanium surfaces, a well-known metal with bone-like mechanical properties that remain stable over time, were used to recreate the pillar nanostructures on the cicadas' wings. The titanium nanopillars have been found to harm P. aeruginosa bacterial cells in a way akin to that of cicada species while being compatible with osteoblast cells, i.e., they are biocompatible for humans. These findings can be leveraged to create the optimal nanostructured surface for biomedical devices, enhancing their bioactivity and bactericidal effectiveness. While such a remarkable discovery paves the way for the development of a new generation of bone implants capable of killing bacteria without the use of antibiotics, the use of nano-textured biomaterial implants in the body still raises concerns about long-term mechanical stability, toxicity and resistance to fracture (Croissant et al., 2017; Jeng & Swanson, 2006)

Figure 5 - Biomimicry enriches the medical industry by inspiring the design of devices based on nature, especially insects (Mitha, 2021).

Conclusions

Placing medical implants in the body raises the risk of bacterial infection. This frequently leads to prolonged hospital stays, costly medical care, the requirement for revision surgery, or even death. It is standard protocol to give patients long-term antibiotic therapy in order to lessen the need of such procedures. However, the antibiotic resistance crisis demands for the development of alternate strategies. Researchers are now aiming to find ways of preventing bacterial infection without the use of antibiotics. Multiple coating technologies are currently available to increase antibacterial features, osseointegration  (bone ingrowth into an implant), and bone regeneration on medical implants; nevertheless, their long-term use is restricted. Although the starting point is promising, additional research must be done before nanotextured orthopedic implants can be used successfully. The rapid and large-scale fabrication of uniform nanostructures is still a challenge. However, it is envisaged that the creation and use of textured, bactericidal orthopedic implants will significantly lower the risk of implant failure brought on by bacterial infection, lowering hospitalization, healthcare expenditures, the requirement for long-term antibiotics, and death rates.

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