Growth hormone-loaded macroporous calcium phosphate ceramic: in vitro biopharmaceutical characterization and preliminary in vivo study.

Calcium phosphate ceramics recently have been used for administering therapeutic agents in bone. The present work investigated the efficacy of macroporous biphasic calcium phosphate (MBCP) implants as a matrix for local delivery of human growth hormone (hGH). An initial study showed that the release of 5 microg of hGH loaded onto MBCP cylinders was rapid during the first 48 h and sustained for a total of 11 days. The biological integrity of hGH (88.2%) was checked using a specific bioassay (cellular proliferation of hGH-sensitive Nb2 cells) in comparison with a radioimmunoassay to calculate the proportion of bioactive hGH released. MBCP cylinders then were loaded with 1, 10, and 100 microg of hGH and implanted into rabbit femurs (n = 16) to determine hGH effects on bone ingrowth and ceramic resorption, as evaluated by scanning electron microscopy and image analysis. Results indicated that hGH increased bone ingrowth and ceramic resorption significantly in comparison with contralateral and control implants. Biochemical parameters monitored in rabbit plasma showed that hGH did not produce detectable systemic effects. Thus the use of MBCP appears to be effective for local delivery of hGH and for increasing bone ingrowth.

[1]  S. J. Holt,et al.  The development of an eluted stain bioassay (ESTA) for human growth hormone. , 1995, Growth regulation.

[2]  N. Araki,et al.  Slow release of anticancer drugs from porous calcium hydroxyapatite ceramic , 1992, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[3]  C. Löwik,et al.  Ceramic hydroxyapatite implants for the release of bisphosphonate. , 1994, Bone and mineral.

[4]  G. Daculsi,et al.  Growth hormone stimulates the degradation of calcium phosphate biomaterial by human monocytes macrophages in vitro. , 1998, Journal of biomedical materials research.

[5]  G. Daculsi,et al.  Association of human growth hormone and calcium phosphate by dynamic compaction: in vitro biocompatibility and bioactivity. , 1997, Journal of biomedical materials research.

[6]  T. Martin,et al.  Growth hormone (GH) receptors in clonal osteoblast-like cells mediate a mitogenic response to GH. , 1991, Endocrinology.

[7]  A. Tencer,et al.  Effect of controlled release of platelet-derived growth factor from a porous hydroxyapatite implant on bone ingrowth. , 1996, Biomaterials.

[8]  K. Kelley.  The Role of Growth Hormone in Modulation of the Immune Response a , 1990, Annals of the New York Academy of Sciences.

[9]  J. Kaufman,et al.  Short and long‐term effects of growth hormone treatment on bone turnover and bone mineral content in adult growth hormone‐deficient males * , 1993, Clinical endocrinology.

[10]  H. Benghuzzi,et al.  Ceramic systems for long-term delivery of chemicals and biologicals. , 1988, Journal of biomedical materials research.

[11]  A. Lindahl,et al.  Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth. , 1987, Endocrine reviews.

[12]  K. Kelley,et al.  A newly defined property of somatotropin: priming of macrophages for production of superoxide anion. , 1988, Science.

[13]  V. Jansson,et al.  Bone formation in coralline hydroxyapatite. Effects of pore size studied in rabbits. , 1994, Acta orthopaedica Scandinavica.

[14]  Y. Ikada,et al.  A bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier. , 1991, The Journal of bone and joint surgery. British volume.

[15]  L. Mosekilde,et al.  Short‐term treatment with growth hormone stimulates osteoblastic and osteoclastic activity in osteopenic postmenopausal women: A dose response study , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[16]  J. Jansson,et al.  Growth hormone stimulates longitudinal bone growth directly. , 1982, Science.

[17]  S. Downes,et al.  Growth-hormone loaded bioactive ceramics , 1991 .

[18]  M. Slootweg,et al.  Growth Hormone and Bone , 1993, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[19]  Michael Jarcho,et al.  Calcium phosphate ceramics as hard tissue prosthetics. , 1981, Clinical orthopaedics and related research.

[20]  N. Araki,et al.  Calcium hydroxyapatite ceramic used as a delivery system for antibiotics. , 1992, The Journal of bone and joint surgery. British volume.

[21]  M. Kumegawa,et al.  Insulin-like growth factor-I supports formation and activation of osteoclasts. , 1992, Endocrinology.

[22]  G. Daculsi,et al.  Macroporous calcium phosphate ceramic for long bone surgery in humans and dogs. Clinical and histological study. , 1990, Journal of biomedical materials research.

[23]  E. Spencer,et al.  Local injections of human or rat growth hormone or of purified human somatomedin-C stimulate unilateral tibial epiphyseal growth in hypophysectomized rats. , 1985, Endocrinology.

[24]  G. Daculsi,et al.  Apatite as carrier for growth hormone: in vitro characterization of loading and release. , 1997, Journal of biomedical materials research.

[25]  R. Marcus,et al.  Effects of recombinant insulin‐like growth factor‐I and growth hormone on bone turnover in elderly women , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[26]  K. Chihara,et al.  Stimulatory effect of growth hormone on bone resorption and osteoclast differentiation. , 1996, Endocrinology.

[27]  L. Mosekilde,et al.  Normal osteoclastic and osteoblastic responses to exogenous growth hormone in patients with postmenopausal spinal osteoporosis , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[28]  P. Cole,et al.  Growth hormone is a human macrophage activating factor. Priming of human monocytes for enhanced release of H2O2. , 1995, Journal of immunology.

[29]  R Z LeGeros,et al.  Biodegradation and bioresorption of calcium phosphate ceramics. , 1993, Clinical materials.

[30]  A. Nilsson,et al.  Systemically and locally administered growth hormone stimulates bone healing in combination with osteopromotive membranes: An experimental study in rats , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.