Biodegradable Systems in Tissue Engineering and Regenerative Medicine

Rui L. Reis, Julio San Román

• Publisher: CRC Press
• Year: 2004
• ISBN:
  9781135494421
• Edition: 1
• Topic: Medicine
• Subtopic: Biochemistry in Medicine

Conventional materials technology has yielded clear improvements in regenerative medicine. Ideally, however, a replacement material should mimic the living tissue mechanically, chemically, biologically and functionally. The use of tissue-engineered products based on novel biodegradable polymeric systems will lead to dramatic improvements in health

Part I
Processing and Applications of Biodegradable Systems

1
Biodegradable Polymers in Medicine

Masakazu Suzuki and Yoshito Ikada

1.1 INTRODUCTION

Medical treatment not only for recovery of diseased regions, but also for restoration to normal functions is not an unrealistic ideal; it has become a practical target. Such medical treatment is called reconstructive surgery and regenerative medicine. Biodegradable polymers are used as materials for reconstructive surgery if the body itself has a potential for cure, because they are absorbed in the body after cure. If the body has no potential for cure, biodegradable polymers are inserted into disordered regions as a scaffold of cells for tissue regeneration, and they disappear after regeneration of tissues.

The first synthesized biodegradable product was poly(glycolic acid) (PGA), which has been studied and produced as a surgical suturing material. With the development of cellular engineering in the 1990s, there have been a number of studies on biodegradable polymers as scaffolds of cells for tissue regeneration.

Natural polymers, such as collagen, which is degraded in the body by enzymes, have been also studied and clinically used. In this chapter, we focus on synthetic biodegradable polymers.

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TABLE 1.1
Characteristics of Biodegradable Monofilament Sutures

1.2 MATERIALS

There have been a number of studies on novel synthetic biodegradable polymers, but most products consist of single polymers and copolymers that have already been used clinically, and many of them are synthetic aliphatic polyesters. Table 1.1 shows the chemical structure of bioabsorbable polymers, which have been clinically used.¹

The period required for absorption markedly differs depending on materials, from 2 to 3 months in PGA to 3 to 5 years in poly(lactic acid) (PLLA). Therefore, different materials are used according to the purpose. The period required for absorption varies even in a single material, depending on the product form such as fiber, film, and sponge; structural factors such as molecular weight and degree of crystallinity; additives and impurities such as residual monomers; and applied regions such as intraosseous, subcutaneous, and intramuscular regions.

1.3 APPLIED FIELDS

Table 1.2 shows the regions where biodegradable polymers have been clinically used or studied, together with their functions.

TABLE 1.2
Functions and Applied Regions of Biodegradable Polymers

Materials Nos. 1 to 4 are for reconstructive surgery and Nos. 5 and 6 are for tissue regeneration. Absorbable materials are also used as carriers in drug delivery systems (DDS), but we are not addressing DDS carriers here.

The products and studies shown in Table 1.2 are described in more detail in the following section.

1.3.1 BIODEGRADABLE POLYMERIC MATERIALS FOR ADHESION AND FIXATION OF TISSUES

1.3.1.1 Sutures

Table 1.3 shows the commercially available absorbable sutures.² The materials are shown in Table 1.1. PGA suture was the first bioabsorbable medical material in the world that was clinically applied and became commercially available. The strength of the PGA suture is reduced to about 50% in 2 weeks, and it disappears in the body in about 3 months. Degradation of sutures without glycolic acid is slow.

Monofilament suture is considered morphologically ideal, and all sutures that have recently been developed and come into the market are monofilament sutures. Since softness of materials is necessary for the monofilament suture, flexible copolymers are used. Figure 1.1 shows the in vivo hydrolytic behavior of the polymeric fibers shown in Table 1.1 as expressed by the retention rate of the tensile strength. This indicates that the degradation rate ranges widely from the high rate of a glycolic acid-å-caprolactone copolymer to the low rate of poly (lactic acid). The factors determining the degradation rate include not only the chemical structure of materials, but also the molecular weight, degree of crystallinity, monomer content, and physical form. Generally, the degradation rate of poly(lactic acid) is low, and that of PGA materials is high.

TABLE 1.3
Commercially Available Absorbable Sutures

FIGURE 1.1 Tensile strength change of resorbable polymer in PBS at 37°C with time.

O PGA (polyglycolide) MONOCRYL (Glycolide-å-caprolactone cop.) BIOSYN (glycolide-ñ-dioxanone-trimethylenecarbonate cop.) MAXON (glycolide-trimethylenecarbonate cop.) P(LA/CL) (L-lactide-å-caprolactone cop.) 75/25 PDS (poly-p-dioxanone) PLLA (poly-L-lactide)

1.3.1.2 Bone Fixation Materials

Metal fixation materials are used for internal fixation of fractured bones. However, since metal corrosion³ sometimes occurred in the body, it was necessary to remove fixation materials after bone union. Furthermore, metal materials such as stainless steel cause artifacts in the commonly used diagnostic MRI, resulting in difficulty in the interpretation. On the other hand, ceramics with bioaffinity have problems in elasticity and fragility.⁴

To improve these drawbacks, bioabsorbable bone fixation materials have been developed. The materials used are poly(p-dioxanone) (PDS), PGA, PLLA, and their copolymers. Currently, bioabsorbable bone fixation materials are produced by more than 10 manufacturers in the world and are widely used clinically. PLLA is the most common material. High strength is required for bone fixation materials, and the development of a processing method for the production of bioabsorbable bone fixation materials with initial strength higher than the living cortical bone resulted in its rapid clinical application.^5,6 In Japan, bioabsorbable bone fixation materials are often used for screw fixation of transplanted bone in acetabular rotary osteotomy and replacement of artificial joints,^7,8 pin-fixation of osseocartilaginous fractures around joints,⁹ and pin-fixation of dissociated ribs.¹⁰ There are many types of bioabsorbable bone fixation materials, and these materials are used in surgical regions where resurgery would be required if metal materials were used for surgery, or in regions where resurgery is difficult to do. Recently, interference screws for the reconstruction of the anterior cruciate ligament and suture anchors for the fixation of the shoulder plate have been clinically used.

1.3.1.3 Adhesives

Table 1.4 shows the properties required for adhesives used in the body.

The most often used adhesive is fibrin glue made of blood-coagulating proteins, which are applied to many regions in various surgical fields. Since the most frequently used fibrin glue is produced from human blood, there is a risk of viral infections. Therefore, a number of studies on its substitutes have been performed. For example, GRF adhesive containing gelatin, resorcinol, formaldehyde, and glutaraldehyde; Advaseal ™¹¹ consisting of copolymers of oligotrimethylene carbonate with polyethylene glycol and acrylate ester terminals, triethanolamine, and a photoinitiator esin Y; and Dermabond ™ containing 2-octyl cyanoacrylate are used for skin adhesion.

TABLE 1.4
Properties Required for Surgical Adhesives

1.3.2 BIODEGRADABLE POLYMER MATERIALS FOR SUPPORT AND REINFORCEMENT OF OTHER MEDICAL DEVICES

To reinforce fragile tissues at the time of suturing, suture reinforcement materials are applied mainly for the lung and air tube in the respiratory apparatus and also for the hepatic parenchyma and digestive tract.¹² Small pieces called predgets were initially used for suture reinforcement and are at present being widely used in the automatic suturing device (mainly used in the U.S. and Japan) for fragile tissues such as the lung.

Fibrous cloth for tissues that can be applied in automatic suturing is increasingly used for fragile tissues. The typical biodegradable biomaterial used for this is Peristrips ™ produced using bovine pericardium. The typical synthetic material is Neoveil ™ made from PGA, which is used for sutures, while Peristrips ™ is used for the pericardium. After biodegradable materials have achieved the desired reinforcement in sutured regions, they will be absorbed in the body, because it is unnecessary to maintain the initial strength.

Thoracotomy or thoracoscopic surgery is performed for the surgical treatment of the respiratory apparatus. The former is applied when a large area of tissues is excised and when it is difficult to obtain a sufficient visual field by thoracoscopy. In such cases, a large-sized fibrous cloth is required and fixed using fibrin glue. The techniques of thoracoscopic surgery are simple, and when the area of excision is limited, this method is effective and can be rapidly performed. The size of the materials used is not larger than that set to an automatic suturing device, and the load on the patient is small.

1.3.3 BIODEGRADABLE POLYMERIC MATERIALS AS TEMPORARY SUBSTITUTES FOR TISSUE

1.3.3.1 Substitutes for the Endocranium

When endocranial defects occur during craniotomy for the treatment of cranial nerves, they must be treated. Therefore, transplantation of autologous tissues, tissues collected from the same or different species, or synthetic dura produced using silicone and polyurethane has been performed. After the outbreak of bovine spongiform encephalopathy in 1996, Creutzfeldt-Jacob disease as a potential infection route of freeze-dried human dura drew attention, and its use was prohibited in Japan in 1997.

Currently, a white elastic e-PTFE sheet, Gore-Tex ™, is the only artificial dura material used in Japan.

Artificial dura using synthetic biodegradable materials such as glycol acid-lactic acid copolymer (Vicryl mesh ™¹³), and Vicryl mesh and collagen film complex¹⁴ have been developed. These dura materials are advantageous compared to nonabsorbable materials when chronic inflammation reac...

Table of contents

• COVER PAGE
• TITLE PAGE
• COPYRIGHT PAGE
• PREFACE
• EDITORS
• CONTRIBUTORS
• PART I: PROCESSING AND APPLICATIONS OF BIODEGRADABLE SYSTEMS
• PART II: PRODUCTION OF BIOMIMETIC COATINGS ON THE SURFACE OF DEGRADABLE POLYMERS
• PART III: SYSTEMS FOR CONTROLLED RELEASE OF BIOACTIVE AGENTS
• PART IV: BIOCOMPATIBILITY AND IMMUNOLOGICAL RESPONSES TO DEGRADABLE BIOMATERIALS
• PART V: BIODEGRADABLE POLYMERS FOR THE ENGINEERING AND REGENERATION OF DIFFERENT TISSUES