Outlook: Innovating synthetic bone graft substitutes
BONESUPPORT’s products can be used whenever there is a need to manage bone voids. The most common causes are revision arthroplasty (after a joint prosthesis fails due to loosening of periprosthetic infection), trauma and osteomyelitis (bone infection) including diabetic foot infections and bone tumours. If treated properly bone is a tissue that can regenerate completely without leaving any scar in the long term (in the short term the healed fracture forms bone callus). This is due to constant remodelling of the bone, a balance maintained by osteoblasts (bone-producing cells) and osteoclasts (cells breaking down and resorbing bone tissue). In certain cases, this process falters and surgical intervention is needed.
Trauma. If the defect is too large or fragments are two far apart, the void will not heal. Complex fractures will often require multiple procedures. Open fractures present a higher risk of infection. In the case of underlying osteoporosis, even simple fractures can be difficult to treat. An estimated c 3.1m procedures to manage simple or complex traumas are performed annually in the US and EU5, with 15-17% involving synthetic bone graft substitute (source: Apex Global Market Study 2016 on behalf of BONESUPPORT).
Osteomyelitis is a difficult-to-treat bacterial infection of the bone tissue. Osteomyelitis can be a primary disease, but will often be a complication of an underlying condition, such as bone fixation procedure after trauma, especially open fracture. If not managed during the acute phase, osteomyelitis can become chronic. An estimated c 80k procedures to manage chronic osteomyelitis are performed annually in the US and EU5, with 22-23% involving synthetic bone graft substitute (source: Apex Global Market Study 2016).
Revision arthroplasty can be subdivided into aseptic loosening and periprosthetic joint infections, both of which are complications of joint replacement procedures. Aseptic loosening can happen over time after the first arthroplasty and revision procedure involves replacing the prosthesis, which often is associated with significant bone loss and difficulties anchoring the new prosthesis. Arthroplasty procedures still carry a small risk of periprosthetic infection (1-2%), which means the prosthesis has to be removed, the infection treated, the bone loss restored with grafting and a new prosthesis implanted. An estimated c 276k revision arthroplasty procedures are performed annually in the US and EU5, with 27-36% involving synthetic bone graft substitute (source as above).
Infected diabetic foot is a specific subtype of osteomyelitis resulting from chronic foot wounds, which are contaminated and colonised by bacteria, which leads to repeated infection and chronic osteomyelitis. Often this results in multiple partial amputations. A total of c 320k procedures involving diabetic foot complications are performed in the US and EU5, with 13-21% involving synthetic bone graft substitutes (source as above).
Tumours and metastases can invade and destroy the bone leaving large voids and weakened bone structure. The treatment can require bone void filling or strengthening the bone with fixators.
Bone voids are treated with bone graft. Initially, this was done using the patient’s own bone from a different location, most often from iliac crests, and remains popular. While such an approach works well, autograft provides a limited amount of bone and requires a separate surgical intervention, which carries risks such as blood loss, infection and pain. Allograft or bone harvested from living or deceased donors could partly solve the quantity issue, but supply is not straightforward as it requires infrastructure (bone banking) and carries risks of disease transmission or bacterial contamination. Bone tissue can also be harvested from animals (xenograft) but, due to concerns about the transmission of infection and other issues related to allografting, it is not very popular. Synthetic bone graft substitutes appeared as a novel alternative and are gaining market share with improving technology.
In addition to providing structure, there are three biological mechanisms for bone grafts involved in bone formation: osteoconduction (graft acts as a scaffold for new bone), osteoinduction (turning undifferentiated cells into osteoblasts) and osteogenesis (new bone tissue production by osteoblasts).
The majority of all bone grafting procedures involve autologous grafts as they work well and historically have been considered the ‘gold standard’ since they are osteoconductive, osteoinductive and osteogenic. However, harvesting involves a second surgical intervention with associated risks such as infection and pain, in addition to the cosmetic effect. Another disadvantage is the limited amount of bone tissue that can be taken.
Allografts are taken from deceased donors or living donors, for example bone banks store femoral heads taken from primary hip arthroplasty procedures. Allografts are osteoconductive, but there is insufficient evidence that osteoinduction and osteogenicity is still present after the processing of the grafts in order to keep them in the bone bank. Other disadvantages include the required infrastructure and potential for disease transmission. Demineralized bone matrix (DBM) is a processed form of allograft retaining much of the protein content of the bone, while reducing mineral content. The original idea was that the protein content, such as growth factors, will act as potent osteogenic/osteoinductive agents. While there are data to some extent supporting better DBM properties compared to allografts, DBM lacks mechanical strength because it is soft and cannot therefore act as a mechanical support.
Synthetic bone graft substitutes are an attractive option as they can be manufactured in unlimited amounts and their mechanical and chemical properties can be tailored, so use is more predictable. Historically, the perceived downside was that they lack the signalling cues present in naturally derived materials, having only an osteoconductive function. BONESUPPORT’s R&D pipeline explores the potential of combining its technology with growth factors to increase osteoinduction and osteogenicity.
While a variety of materials can be used for synthetic bone graft, ceramic materials are the most common choice and are based on forms of calcium sulfate, calcium phosphate or combinations. Calcium sulfate was the first material used in synthetic bone graft substitutes. However, the main drawback was quick resorption over six to eight weeks and lack of bone growth support. The addition of calcium phosphate substantially improved resorption time and during the last two decades different combinations of these materials have been explored in various forms. CERAMENT is 60% calcium sulfate and 40% hydroxyapatite (a form of calcium phosphate). BONESUPPORT has shown a clinically balanced resorption rate (see CERAMENT BVF section below) that matches the formation of new bone tissue, allowing time for bone remodelling.
Other materials used less frequently for synthetic bone graft substitution include bioglass, degradable and non-degradable polymers and other biomaterials.
Innovation in bone graft substitution: Managing infections
Risk of infection in trauma and orthopaedic surgery is a particular concern. Around 30% of open fractures and 2-5% of closed fractures treated surgically become infected. The percentage is much smaller in joint replacement procedures (1-2%), although this is still a major issue. For example, if a joint prosthesis becomes infected after the primary replacement operation, the common two-stage treatment involves complete removal of the device, debridement of the necrotic tissue, leaving an antibiotic-loaded cement spacer, treatment of the infection with systemic antibiotic therapy and then repeated arthroplasty. This means primary arthroplasty is wasted, which is costly, as well as highly invasive for the patient, and repeated arthroplasty is complicated as a significant amount on bone can be lost while removing the primary prosthesis, which has been firmly anchored in the bone.
In the case of infection, antibiotics can be delivered systemically or/and locally. While there are various materials used for the delivery of antibiotics locally, in situations where bone grafting is needed, the combination of a bone graft substitute is a natural solution. Osteoset-T (Wright Medical) was the first synthetic bone graft substitute based on calcium sulfate with added antibiotic tobramycin and was CE marked in the late 1990s. However, as discussed above, standalone calcium sulfate is not an ideal synthetic bone substitute. It is minimally osteoconductive, quickly resorbing and not injectable. BONESUPPORT’s two products with added vancomycin and gentamicin, CERAMENT V and CERAMENT G, have the same properties of the backbone CERAMENT technology in addition to an antibiotic-eluting property. According to the company and to our knowledge, currently these two products are the only ones available with in an injectable form and a CE mark.