The effect of lysophosphatidic acid using a hydrogel or collagen sponge carrier on bone healing in dogs

Kelly R. Might; Steven A. Martinez; Norman Karin; Genyao Lin; Barbara Tarasevich; Roy R. Pool

doi:10.3415/VCOT-15-08-0137

Veterinary and Comparative Orthopaedics and Traumatology, Inhaltsverzeichnis

Vet Comp Orthop Traumatol 2016; 29(04): 306-313
DOI: 10.3415/VCOT-15-08-0137

Original Research

Schattauer GmbH

The effect of lysophosphatidic acid using a hydrogel or collagen sponge carrier on bone healing in dogs

Autor*innen

Kelly R. Might

¹Comparative Orthopedics Research Laboratory, Washington State University, Pullman, WA, USA

⁶Current: Mobile Veterinary Specialist, Austin, TX, USA
Steven A. Martinez

¹Comparative Orthopedics Research Laboratory, Washington State University, Pullman, WA, USA
Norman Karin

²University of Buffalo, Roswell Park Cancer Institute, Buffalo, NY, USA
Genyao Lin

³Solvay, Leetsdale, PA, USA
Barbara Tarasevich

⁴Pacific Northwest National Laboratory, Richland, WA, USA
Roy R. Pool

⁵Texas A&M University, College of Veterinary Medicine and Biomedical Sciences, Department of Veterinary Pathobiology, College Station, TX, USA

Abstract

Summary

Objectives: The purposes of this study were to determine: 1) the efficacy of polycaprolac-tone-g-polyethylene glycol (PCL-g-PEG) and polylactic-co-glycolic acid (PLGA-g-PEG) hydrogels and an absorbable collagen sponge (ACS) as carriers for lysophosphatidic acid (LPA), 2) the effect of LPA on bone healing in dogs, and 3) the ideal dose of LPA to maximally stimulate bone healing.

Methods: Bilateral ulnar ostectomies were performed on purpose bred dogs. Control defects were filled with a PCL-g-PEG or PLGA-g-PEG hydrogel, or a saline soaked ACS. Contralateral defects were filled with a PCL-g-PEG or PLGA-g-PEG hydrogel, or an ACS with each carrying differing concentrations of an LPA solution. Dual-energy X-ray absorptiometry (DXA) was performed. Total bone area (TBA), mineral density (BMD), and mineral content (BMC) were determined at each time point. Relationships between the effect of treatment over time on TBA, BMC and BMD were determined.

Results: Phase 1 - There was no significant difference in DXA-based TBA (p = 0.09), BMC (p = 0.33), or BMD (p = 0.74) over time between LPA treatments, or between the LPA treated and control groups TBA (p = 0.95), BMC (p = 0.99), or BMD (p = 0.46). Phase 2 - There was no significant difference over time between LPA treatments in DXA-based TBA (p = 0.33), BMC (p = 0.45), or BMD (p = 0.43), or between the LPA treated and control groups TBA (p = 0.94), BMC (p = 0.38), or BMD (p = 0.17). Phase 3 - There was no significant difference over time between LPA treatments in DXA-based TBA (p = 0.78), BMC (p = 0.88), or BMD (p = 0.35), or between the LPA treated and control groups TBA (p = 0.07), BMC (p = 0.85), or BMD (p = 0.06). There was a significant increase in TBA (p <0.0001) and BMC (p = 0.0014), but a significant decrease in BMD (p <0.0001) was noted over time when all groups were combined.

Clinical significance: Although LPA has shown promise as an osteoinductive agent in research, its performance as a bone graft substitute, as utilized in this study, is unsupported. Further studies are necessary to determine the incorporation and elution kinetics of LPA from the PLGA-g-PEG hydrogel and from an ACS. Hydrogels may have clinical applications for delaying or preventing bone formation.

Keywords

Lysophosphatidic acid - hydrogel - polycaprolactone - bone healing - osteogenesis

Volltext

Referenzen

References
1 Finkemeier CG. Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am 2002; 84: 454-464.
2 Bonfiglio M, Jeter W. Immunological responses to bone. Clin Orthop Relat Res 2013; 87: 19-27.
3 Williams A, Szabo RM. Bone transplantation. Orthop 2004; 27: 488-495.
4 Lissenberg-Thunnissen SN, Gorter DJJ, Sier CFM. et al. Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop 2011; 35: 1271-1280.
5 Nietgen GW, Durieux ME. Intercellular signaling by lysophosphatidate. Recent developments. Cell Adhes Commun 1998; 5: 221-235.
6 Eichholtz T, Jalink K, Fahrenfort I. et al. The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem J 1993; 291: 677-680.
7 Fukami K, Takenawa T. Phosphatidic acid that accumulates in platelet-derived growth factor-stimulated Balb/c 3T3 cells is a potential mitogenic signal. J Biol Chem 1992; 267: 10988-10993.
8 Fourcade O, Simon MF, Viodé C. et al. Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell 1995; 80: 919-927.
9 van Dijk MC, Postma F, Hilkmann H. et al. Exogenous phospholipase D generates lysophosphatidic acid and activates Ras, Rho and Ca2+ signaling pathways. Curr Biol 1998; 8: 386-392.
10 Balazs L, Okolicany J, Ferrebee M. et al. Topical application of the phospholipid growth factor lysophosphatidic acid promotes wound healing in vivo. Am J Physiol Regul Integr Comp Physiol 2001; 280: R466-472.
11 Demoyer JS, Skalak TC, Durieux ME. Lysophosphatidic acid enhances healing of acute cutaneous wounds in the mouse. Wound Repair Regen 2000; 8: 530-537.
12 Caverzasio J, Palmer G, Suzuki A. et al. Evidence for the involvement of two pathways in activation of extracellular signal-regulated kinase (Erk) and cell proliferation by Gi and Gq protein-coupled receptors in osteoblast-like cells. J Bone Miner Res 2000; 15: 1697-1706.
13 Dziak R, Yang BM, Leung BW. et al. Effects of sphingosine-1-phosphate and lysophosphatidic acid on human osteoblastic cells. Prostaglandins Leukot Essent Fatty Acids 2003; 68: 239-249.
14 Grey A, Banovic T, Naot D. et al. Lysophosphatidic acid is an osteoblast mitogen whose proliferative actions involve G(i) proteins and protein kinase C, but not P42/44 mitogen-activated protein kinases. Endocrinology 2001; 142: 1098-1106.
15 Grey A, Chen Q, Callon K. et al. The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase. Endocrinology 2002; 143: 4755-4763.
16 Masiello LM, Fotos JS, Galileo DS. et al. Lysophosphatidic acid induces chemotaxis in MC3T3-E1 osteoblastic cells. Bone 2006; 39: 72-82.
17 Gidley J, Openshaw S, Pring ET. et al. Lysophosphatidic acid cooperates with 1α,25(OH)2D3 in stimulating human MG63 osteoblast maturation. Prostaglandins Other Lipid Mediat 2006; 80: 46-61.
18 Rivera-Lopez CM, Tucker AL, Lynch KR. Lysophosphatidic acid (LPA) and angiogenesis. Angiogenesis 2008; 11: 301-310.
19 Silva AK, Richard C, Bessodes M. et al. Growth factor delivery approaches in hydrogels. Biomacromolecules 2009; 10: 9-18.
20 Peppas NA, Bures P, Leobandung W. et al. Hydrogels in pharmaceutical formulations. Europ J Pharm Biopharm 2000; 50: 27-46.
21 Tayalia P, Mooney DJ. Controlled growth factor delivery for tissue Engineering. Adv Mater 2009; 21: 3269-3285.
22 Friess W, Uludag H, Foskett S. et al. Characterization of absorbable collagen sponges as rhBMP-2 carriers. Int J Pharm 1999; 187: 91-99.
23 Lin G, Cosimbescu L, Karin NJ. et al. Injectable and thermogelling hydrogels of PCL-g-PEG: mechanisms, rheological and enzymatic degradation properties. J Mater Chem B 2013; 1: 1249-1255.
24 Lin G, Cosimbescu L, Karin NJ. et al. Injectable and thermosensitive PLGA-g-PEG hydrogels containing hydroxyapatite: preparation, characterization and in vitro release behavior. Biomed Mater 2012; 7: 024107
25 Karagiosis SA, Karin NJ. Lysophosphatidic acid induces osteocyte dendrite outgrowth. Biochem Biophys Res Commun 2007; 357: 194-199.
26 Albilia JB, Tenenbaum HC, Clokie CM. et al. Serum levels of BMP-2, 4, 7 and AHSG in patients with degenerative joint disease requiring total arthroplasty of the hip and temporomandibular joints. J Orthop Res 2013; 31: 44-52.
27 Park MC, Park YB, Lee SK. Relationship of bone morphogenetic proteins to disease activity and radiographic damage in patients with ankylosing spondylitis. Scand J Rheumatol 2008; 37: 200-204.
28 Schmitt JM, Hwang K, Winn SR. et al. Bone morphogenetic proteins: an update on basic biology and clinical relevance. J Orthop Res 1999; 17: 269-278.
29 Jeong B, Windisch CF, Park MJ. et al. Phase transition of the PLGA-g-PEG copolymer aqueous solutions. J Phys Chem B 2003; 107: 10032-10039.
30 Niehaus AJ, Anderson DE, Samii VF. et al. Effects of orthopedic implants with a polycaprolactone polymer coating containing bone morphogenetic protein-2 on osseointegration in bones of sheep. Am J Vet Res 2009; 70: 1416-1425.
31 Lam CX, Savalani MM, Teoh SH. et al. Dynamics of in vitro polymer degradation of polycaprolactone-based scaffolds: accelerated versus simulated physiological conditions. Biomed Mater 2008; 3: 034108
32 Geng Y, Discher DE. Hydrolytic degradation of poly(ethylene oxide)-block-polycaprolactone worm micelles. J Am Chem Soc 2005; 127: 12780-12781.
33 Vandewater A, Olmstead ML, Stevenson S. Partial ulnar ostectomy with free autogenous fat grafting for treatment of radius curvus in the dog. Vet Surg 1982; 11: 92-99.