Gene Therapy in Bone Regeneration: A Summary of Delivery Approaches for Effective Therapies - Intracellular Delivery: Fundamentals and Applications - page 815

fibroblast growth factors (Scmid et al. 2009 ). Failure during the sequence of events
leads to either a hypertrophic or atrophic non-union. Hypertrophic non-unions have a
robust blood supply and the capacity to fully heal. In contrast, atrophic non-unions
have poor vascularisation and are incapable of biological response needed for success-
ful healing. In the case of atrophic non-union, de novo bone regeneration is required.
Thus, the clinical challenge is to address these failures of biology and to intervene
with therapeutics that can restore and/or stimulate natural healing response.

2 Current Treatment of Non-unions

and Use of Bioactive Agents for Bone Regeneration

Autologous bone grafts remain the gold standard for non-union bone defects,
where tissue from another site, usually the iliac crest, is harvested to repair the
defect. Assuming the quantity and quality of bone harvested are sufficient, pain,
second-site morbidity and risks associated with a second surgical site present
obstacles to be overcome. Allografts are used as a viable alternative to autografts;
both the US Food and Drug Administration and American Associated of Tissue
Banks works to develop standardized procedures for harvest, sterilization and
storage of tissue suitable for grafting (Cook and Cook 2009 ). The quality of
allografts varies greatly; extensive processing helps to decrease the likelihood of
disease transmission, but it also reduces the osteogenic potential of the graft while
increasing the variation in their bone induction capability. However, the risk of
disease transmission remains high despite extensive graft processing, screening and
sterilization. Synthetic biomaterials, such as hydroxyapatite (HA) or collagen-
based bone substitutes, are another option as bone implants, but they are only
osteoconductive and therefore not ideal for large defects where bone ingrowth from
the surrounding tissue needs to be extensive. HA and other calcium phosphate
cements generally lack appropriate mechanical properties for bone, as their brittle-
ness leaves them prone to fracture very easily. Demineralized bone matrix, decalci-
fied cortical bone, has demonstrated to be successful in bone grafting but their
success is sporadic and not always guaranteed, which has been attributed to the
differences in processing of the bone tissues. Although thoroughly processed,
demineralised bone matrix still contains certain growth factors that make this
biomaterial osteoinductive (i.e., capable of inducing de novo bone from the
surrounding/infiltrating mesenchymal stem cells). One group of the proteins respon-
sible for the osteoinductivity of demineralised bone matrix is the bone morphoge-
netic proteins (BMP), first discovered by Marshall Urist ( 1956 ). This group of
proteins is best known for its ability to induce ectopic bone formation in the
absence of any bone tissue at the implant site. At lower femtomolar concentrations,
BMP-2 can act as a chemotactic agent attracting cells (Feidler et al. 2002 ); however,
at high concentrations, BMPs act as a morphogen, causing stem cells to differentiate
to an osteogenic fate. There are several BMP-based therapies approved for ortho-
paedic applications, where BMP-2 and BMP-7 (also known as Osteogenic Protein-1
or OP-1) are the bioactive ingredients.