**7. Biomaterials**

Implantation of biomaterial is useful to provide initial strength to avoid collapse of the femoral head. Recent development of biomaterials aims to implement osteoinduction and osteocon‐ duction ability in biomaterials themselves [58, 59]. Tantalum rods have high volumetric porosity, providing excellent osteoconductive properties, while their elastic modulus is similar to that of bone, providing exceptional biocompatibility [60]. In their case series of 50 hips treated with tantalum rods, Veillette et al. [61] reported a conversion rate to total hip arthro‐ plasty in only 15.5% of their cases. Miao et al. [62] compared tantalum rod implantation to core decompression in patients with the early stage FHN (i.e., Steinberg stage 1 or 2) hips. After treatment, clinical score on radiographic assessment was improved in both the treatment groups. Pakos et al. [63] used tantalum rods with bone marrow and autologous bone grafting to treat patients with Steinberg stage 2 or stage 3 FHN. Five years after treatment, only 3% of hips in stage 2 and 15% in stage 3 were converted to total hip replacement.

Other biodegradable materials have also been used. Nano-hydroxyapatite/polyamide (n-HA/ PA) 66 rods were used for the treatment of FHN [61, 64]. In their case series of 84 FHN cases, Yang et al. [64] allocated patients to two treatment groups, the first combining core decom‐ pression in combination with insertion of a n-HA/PA 66 rod and the second combining core decompression with an autologous cancellous bone graft. In the n-HA/PA 66 rod group, 21.1% of hips progressed to collapse of the femoral head, compared to 45.7% in the bone grafting group. A distinct advantage of biomaterials is their ability to change their form to easily fill cavities of different shapes. The clinical benefits of different biomaterials in the treatment of hips with FHN have been reported: Yamasaki et al. [31] used rod type porous hydroxyapatite; Liu et al. [32] used composite filler; and Aoyama et al. [47] and Kawate et al. [48] used porous beta-tricalcium phosphate granules in combination with cultured MSCs. Although there is evidence of satisfactory clinical outcomes using biomaterials, when these materials are used in combination with cell transplantation, the balance between the timing of degradation and osteogenesis is an important factor influencing outcome. Specifically, the activity of osteoclasts has been shown to be influenced by the type of biomaterial [65]. In the presence of biomaterials that facilitate early resorption of bone, compared to bone formation, the biomaterial does not have sufficient strength to protect against collapse. Therefore, the combination between biomaterial and cell type needs to be carefully examined.

### **8. Growth factors**

there is a dysregulation of the balance between osteoclast and osteoblast activity [35, 54]. In FHN, both living osteoclast and osteoblast cells are reduced in number. Therefore, pathogenic tissue, such as necrotic bone, should be removed as a component of treatment to facilitate bone remodeling. MSCs have the ability not only to differentiate into osteogenic cells, but they can also stimulate the osteoclastogenesis [55–57]. Therefore, the cytokine effect of MSCs induces a

Implantation of biomaterial is useful to provide initial strength to avoid collapse of the femoral head. Recent development of biomaterials aims to implement osteoinduction and osteocon‐ duction ability in biomaterials themselves [58, 59]. Tantalum rods have high volumetric porosity, providing excellent osteoconductive properties, while their elastic modulus is similar to that of bone, providing exceptional biocompatibility [60]. In their case series of 50 hips treated with tantalum rods, Veillette et al. [61] reported a conversion rate to total hip arthro‐ plasty in only 15.5% of their cases. Miao et al. [62] compared tantalum rod implantation to core decompression in patients with the early stage FHN (i.e., Steinberg stage 1 or 2) hips. After treatment, clinical score on radiographic assessment was improved in both the treatment groups. Pakos et al. [63] used tantalum rods with bone marrow and autologous bone grafting to treat patients with Steinberg stage 2 or stage 3 FHN. Five years after treatment, only 3% of

Other biodegradable materials have also been used. Nano-hydroxyapatite/polyamide (n-HA/ PA) 66 rods were used for the treatment of FHN [61, 64]. In their case series of 84 FHN cases, Yang et al. [64] allocated patients to two treatment groups, the first combining core decom‐ pression in combination with insertion of a n-HA/PA 66 rod and the second combining core decompression with an autologous cancellous bone graft. In the n-HA/PA 66 rod group, 21.1% of hips progressed to collapse of the femoral head, compared to 45.7% in the bone grafting group. A distinct advantage of biomaterials is their ability to change their form to easily fill cavities of different shapes. The clinical benefits of different biomaterials in the treatment of hips with FHN have been reported: Yamasaki et al. [31] used rod type porous hydroxyapatite; Liu et al. [32] used composite filler; and Aoyama et al. [47] and Kawate et al. [48] used porous beta-tricalcium phosphate granules in combination with cultured MSCs. Although there is evidence of satisfactory clinical outcomes using biomaterials, when these materials are used in combination with cell transplantation, the balance between the timing of degradation and osteogenesis is an important factor influencing outcome. Specifically, the activity of osteoclasts has been shown to be influenced by the type of biomaterial [65]. In the presence of biomaterials that facilitate early resorption of bone, compared to bone formation, the biomaterial does not have sufficient strength to protect against collapse. Therefore, the combination between

hips in stage 2 and 15% in stage 3 were converted to total hip replacement.

biomaterial and cell type needs to be carefully examined.

healthy remodeling regulation.

98 Advanced Techniques in Bone Regeneration

**7. Biomaterials**

Growth factors, such as transforming growth factor-β1, platelet-derived growth factor, vascular endothelial growth factors, fibroblast growth factor-2 (FGF-2), and bone morphoge‐ netic protein (BMP) treatment, aim to promote revascularization and bone formation in hips with FHN [66]. Samara et al. [67] reported a lower expression of BMP-2 and BMP-6 in the femoral head of patients with FHN, compared to healthy controls. Therefore, supplying the lacking growth factor may be a reasonable adjunct treatment option. Lieberman et al. [68] used BMP-2 replacement in combination with allogenic fibula transplantation, reporting a radio‐ graphic progression of FHN in 17.6% of hips in Ficat stages 2 and 3. Sun et al. [69] compared the outcomes of recombinant BMP-2 treatment in combination with artificial bone implanta‐ tion to implantation of artificial bone alone. The radiographic survival rate of the femoral head for hips in the BMP-2 treatment group was 100.0% for ARCO stage 2b hips, 84.2% for ARCO stage 2C hips, and 30.0% for ARCO stage 3 hips. By comparison, in the control group treated by implantation alone, the survival rate was 100.0% for ARCO stage 2b, 76.5% for ARCO stage 2C, and 37.5% for ARCO stage 3. Sun et al. concluded that BMP-2 was effective for selected patients. Papanagiotou et al. [70] used BMP-7 in combination with autologous, nonvascular‐ ized fibular grafting for hips in Steinberg stage 2 or stage 3. Over a 4-year follow-up, 29% of hips progressed to collapse and required total hip replacement. Papanagiotou et al. did report that BMP-7 in combination with autologous, nonvascularized, fibular grafting, is effective for shortening operative time and the postoperative rehabilitation period. Kuroda et al. [71] used recombinant FGF-2 impregnated with gelatin hydrogel for minimally invasive surgical treatment of patients in early stages of FHN. In their case series, 10% of hips progressed to collapse 1-year posttreatment, with improvement in radiographic clinical score in all other cases. Results of these preliminary studies provide evidence of the safety and feasibility of treatment using growth factors. Abe et al. [72] also reported elevation in levels of interleukin-6 and tumor necrosis factor-α in the joint fluid of hip in advanced stages of FHN. Therefore, modulation of cytokine activity, in combination with growth factors, may be an effective treatment strategy. Therefore, although there is currently no clinical report combining cellbased therapy and growth factor treatment, this combination holds promise for treatment of FHN and should be evaluated in future studies.

#### **9. Conclusion**

For an effective treatment of FHN, an osteogenic cell supply, revascularization, and providing initial strength to resist collapse are needed. The combination of cell-based therapy, growth factor, and biomaterial may effectively meet these requirements [73]. The development of new procedures is required, with treatment being according to the pathology and clinical status being extremely important considerations.
