bone defects

Regional Gene Therapy with Transduced Human Cells: The Influence of “Cell Dose” on Bone Repair

AUTHORS

Hansel Ihn, Hyunwoo Kang, Brenda Iglesias, Osamu Sugiyama, Amy Tang, Roger Hollis, Sofia Bougioukli, Tautis Skorka, Sanghyun Park, Donald Longjohn, Daniel A. Oakes, Donald B. Kohn, and Jay R. Lieberman

ABSTRACT

Regional gene therapy using a lentiviral vector containing the BMP-2 complementary DNA (cDNA) has been shown to heal critical-sized bone defects in rodent models. An appropriate “cellular dose” needs to be defined for eventual translation into human trials. The purpose of this study was to evaluate bone defect healing potential and quality using three different doses of transduced human bone marrow cells (HBMCs). HBMCs were transduced with a lentiviral vector containing either BMP-2 or green fluorescent protein (GFP). All cells were loaded onto compression-resistant matrices and implanted in the bone defect of athymic rats. Treatment groups included femoral defects that were treated with a low-dose (1 × 106 cells), standard-dose (5 × 106 cells), and high-dose (1.5 × 107 cells) HBMCs transduced with lentiviral vector containing BMP-2 cDNA. The three control groups were bone defects treated with HBMCs that were either nontransduced or transduced with vector containing GFP. All animals were sacrificed at 12 weeks. The bone formed in each defect was evaluated with plain radiographs, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing. Bone defects treated with higher doses of BMP-2-producing cells were more likely to have healed (6/14 of the low-dose group; 12/14 of the standard-dose group; 14/14 of the high-dose group; χ2(2) = 15.501, p < 0.001). None of the bone defects in the control groups had healed. Bone defects treated with high dose and standard dose of BMP-2-producing cells consistently outperformed those treated with a low dose in terms of bone formation, as assessed by microCT and histomorphometry, and biomechanical parameters. However, statistical significance was only seen between defects treated with high dose and low dose. Larger doses of BMP-2-producing cells were associated with a higher likelihood of forming heterotopic ossification. Femurs treated with a standard- and high-dose BMP-2-producing cells demonstrated similar healing and biomechanical properties. Increased doses of BMP-2 delivered through higher cell doses have the potential to heal large bone defects. Adapting regional gene therapy for use in humans will require a balance between promoting bone repair and limiting heterotopic ossification.

Injectable sericin based nanocomposite hydrogel for multi-modal imaging-guided immunomodulatory bone regeneration

AUTHORS

Li-Bo Jiang, Sheng-Long Ding, Wang Ding, Di-Han Su, Fang-Xue Zhang, Tai-Wei Zhang, Xiao-Fan Yin, Lan Xiao, Yu-Lin Li, Feng-Lai Yuan, Jian Dong

ABSTRACT

Irregular bone defects, where the inflammation and immune microenvironment confronted with implanted biomaterials, remain a prominent challenge for bone regeneration. In this study, we fabricated an injectable alginate/sericin/graphene oxide (Alg/Ser/GO) hydrogel based on the Alg–Tyramine framework with HRP/H2O2 enzymatic crosslinking. This hydrogel exhibited bioimaging property and controlled degradation behavior upon releasing sericin and GO. Importantly, synergistic effects on bone regeneration between sericin and GO were demonstrated. GO significantly enhanced the spreading, osteogenic differentiation, and mineralization of encapsulated rat BMSCs, whereas the released sericin promoted M2 polarization and migration via the NF-κB and MAPK pathways. The M2 polarization of macrophages induced osteogenic differentiation of BMSCs via several secreted cytokines. Both in vivo and in vitro experiments showed that the Alg/Ser/GO hydrogel induced macrophage infiltration into the surrounding tissues and inhibited inflammation and fibrous capsule thickening. Last, the injected Alg/Ser/GO hydrogels with BMSCs promptly repaired established distal femoral defects in rats. Therefore, the fabricated Alg/Ser/GO hydrogel, along with macrophages and BMSCs, is a promising biomaterial for bone healing, especially the irregular bone defects.

Built-In Electric Fields Dramatically Induce Enhancement of Osseointegration

Rapid and effective osseointegration is a great challenge in clinical practice. Endogenous electronegative potentials spontaneously appear on bone defect sites and mediate healing. Thus, bone healing can potentially be stimulated using physiologically relevant electrical signals in implants. However, it is difficult to directly introduce physiologically relevant electric fields in bone tissue.

A novel nonviral gene delivery tool of BMP-2 for the reconstitution of critical-size bone defects in rats

The osseointegration of bone implants, implant failure, and the bridging of critical-size bone defects are frequent clinical challenges. Deficiencies in endogenous bone healing can be resolved through the local administration of suitable recombinant growth factors (GFs).