Controlled release of platelet-derived growth factor from porous poly(l-lactide) membranes for guided tissue regeneration

doi:10.1016/S0168-3659(97)00169-7

Journal of Controlled Release

Volume 51, Issues 2–3, 12 February 1998, Pages 201-211

https://doi.org/10.1016/S0168-3659(97)00169-7 Get rights and content

Abstract

Platelet-derived growth factor-BB (PDGF-BB) was incorporated into porous poly (l-lactide) (PLLA) membranes with an aim of improving early bone healing in guided tissue regeneration (GTR) therapy. Porous PDGF-BB loaded membranes were fabricated by coating PDGF-BB-dissolved PLLA methylene chloride–ethyl acetate solutions on polyglycolic acid (PGA) meshes. Release kinetics of PDGF-BB, biologic activity, degradability and guided tissue regenerative potentials of the membranes were investigated. Release of PDGF-BB could be controlled by adding bovine serum albumin that may provide porous diffusion channels for PDGF-BB release and by varying initial loading content of PDGF-BB. Biologic activity of PDGF-BB in the membranes was ascertained by fibroblast chemotaxis. PDGF-BB loaded membranes maintained proper degradation property for periodontal application. PDGF-BB loaded membrane markedly increased new bone formation in rat calvarial defects, and completed bony reunion after 2 weeks of implantation period. These results suggested that PDGF-BB loaded PLLA membrane might potentially enhance guided tissue regenerative efficacy.

Introduction

Guided tissue regeneration (GTR) technique by using barrier membranes has been suggested as a potential modality in periodontal therapy 1, 2, 3. These barrier membranes prevent apical migration of gingival epithelial cells into bony defect site and promote growth of progenitor bone and periodontal ligament cells. Membranes for this purpose include GORE-TEX^® [4], collagen membrane [5], Vicryl Periodontal Mesh [6], polylactic acid sheet [7], Guidor^® [8], and demonstrated successful periodontal regeneration. General requirements for the barrier membranes in GTR process are suitable mechanical stability, optimal porosity and biodegradability. Mechanical stability is related to membrane barrier function for selective cell growth during implantation period. Porous structure both at the surface and sublayer of the membranes is essential for cellular adaptation and sufficient nutrient permeation. Nonbiodegradable membranes such as GORE-TEX^® required secondary surgical procedure for retrieval and this remains a significant drawback. Thus many researchers have assessed the value of biodegradable membranes. These biodegradable membranes received high interest for clinical trials.

Recent studies have provided evidences that drugs, i.e. flurbiprofen 9, 10, tetracycline 11, 12and some growth factors 13, 14, 15, 16, 17improve the early healing process and regeneration of lost periodontal tissue. Especially, growth factors such as platelet-derived growth factor (PDGF) 13, 14, 15, insulin-like growth factor (IGF), transforming growth factor (TGF) may function as regulators of proliferation, chemotaxis and differentiation of various pluripotent cells 15, 16, 17. Periodontal regeneration was enhanced by using growth factors in beagle dog and monkey 18, 19, 20. However, as yet, extremely high dose of PDGF-BB (3000–5000 ng) has been applied in clinical trials owing to rapid clearance of PDGF-BB in vivo and inability to maintain therapeutic concentration during implantation period. Therefore, controlled growth factor delivery from barrier membrane may be highly beneficial for the treatment of periodontal disease. Porous poly-l-lactide (PLLA) membranes have been developed in our laboratories and controlled drug releasing techniques using these membranes was reported [21].

In this study, PDGF-BB was selected as a model growth factor that stimulate mitogenesis and proliferation in mesenchymal-derived cells including fibroblasts, ligament cells and osteoblasts [13]. The aim of this study was to design PDGF-BB releasing porous PLLA membranes for GTR. PDGF-BB release mechanism, activity of PDGF-BB, degradation property and guided bone regeneration potential will be discussed in this paper.

Section snippets

Materials

PLLA (MW 370 000) was purchased from Purac Biochem BV, Gorinchem, Netherlands. Viscosity measurement at 25°C of the PLLA dissolved in chloroform gave an intrinsic viscosity of 6.30 dl/g. Polyglycolic acid (PGA) meshes were supplied by Sam Yang Group R and D center, Taejeon, Korea. PDGF-BB and $^{125} I$ -labelled PDGF-BB were purchased from Genzyme Co., Cambridge, USA and Amersham, UK, respectively. Bovine serum albumin (BSA) was obtained from Sigma, MO, USA. Span 80 was purchased from Showa

Morphology of PDGF-BB loaded PLLA membranes

Scanning electron microscopes of PDGF-BB loaded porous PLLA membranes are shown in Fig. 1. Pore generation was successfully achieved not only on the surface but also in the sublayer of the PLLA membrane. In-air drying phase inversion process was suited for the fabrication of PDGF-BB loaded porous membranes [21], and the emulsified PDGF-BB did not affect pore morphology.

Release of PDGF-BB from porous PLLA membranes

Fig. 2 demonstrates the release profile of PDGF-BB from porous PLLA membranes varying the BSA contents. In this experiment,

Conclusion

PDGF-BB loaded porous PLLA membranes fabricated by using in-air drying phase inversion technique may be effective for controlled PDGF-BB releasing system and physical barriers as well. PDGF-BB in the membrane retained its biological activity and the release rate of PDGF-BB could be controlled for optimal therapeutic effects in GTR. PDGF-BB released from PLLA membrane enhanced the early bone healing and regeneration. The PDGF-BB loaded porous PLLA membranes might be a valuable modality in

Acknowledgements

The authors are thankful to Sam Yang Group R and D Center for providing materials. This work was supported by the grant of Korea Science and Engineering Foundation (KOSEF) #94-0403-05-02-3, Korea.

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Citation Excerpt :
Furthermore, they showed the release of PDGF-BB to be enhanced as the BSA content increased. The release of 100 ng PDGF-BB loaded membrane containing BSA (10%) was almost the same as that from 200 ng PDGF-BB loaded membrane without BSA (Park et al., 1998). Heparinization of the membranes also affects the GF release properties.
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A total of 138 articles were screened in PubMed databases, and 31 meeting the inclusion criteria were included in the present systematic review.
All the articles evaluated bio-resorbable membranes, especially collagen or polymer-based membranes. In most studies, the retention and release kinetics of osteogenic GFs such as BMP-2 and PDGF were widely investigated. Growth factors were incorporated to the membranes by soaking and incubating the membranes in GF solution, followed by lyophilization, or mixing in the polymers before evaporation. Adsorption onto the membranes depended upon the membrane materials and additional reagents such as heparin, cross-linkers and GF concentration. Interestingly, most studies showed two phases of GF release from the membranes: a first phase comprising a burst release (about 1 day), followed by a second phase characterized by slower release. Furthermore, all the studies demonstrated the controlled release of sufficient concentrations of GFs from the membranes for bioactivities.
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Controlled release of platelet-derived growth factor from porous poly(l-lactide) membranes for guided tissue regeneration

Abstract

Introduction

Section snippets

Materials

Morphology of PDGF-BB loaded PLLA membranes

Release of PDGF-BB from porous PLLA membranes

Conclusion

Acknowledgements

J. Control. Release

Advanced Drug Delivery Reviews

J. Control. Release

J. Pharm. Sci.

J. Control. Release

The regenerative potential of the periodontal ligament. An experimental study in the monkey

J. Clin. Periodontol.

Osteopromotion: A soft-tissue exclusion principle using a membrane for bone healing and bone neogenesis

J. Periodontol.

Evaluation of guided tissue regeneration in class II furcation defects. A clinical reentry study

J. Periodontol.

Periodontal repair in dogs: Expanded polytetrafluoroethylene barrier membranes support wound stabilization and enhance bone regeneration

J. Periodontol.

Collagen membrane barrier therapy to guided regeneration in class II furcations in humans

J. Periodontol.

Regeneration of lost attachment apparatus in the dog using Vicryl absorbable mesh (Polyglactin 910)

Int. J. Periodont. Restorative Dent.

Histologic evaluation of periodontal attachment apparatus following the insertion of a biodegradable copolymer barrier in humans

J. Periodontol.

New attachment formation in the monkey using GUIDOR, a bioresorbable GTR device

J. Dent. Res.

Indomethacin or flurbiprofen treatment of periodontitis in beagles

J. Periodont. Res.

Flurbiprofen treatment of human periodontitis

J. Periodont. Res.