Formation of highly porous biodegradable scaffolds
for tissue engineering

Antonios G. Mikos^*
Department of Bioengineering, Rice University
6100 Main, MS 142, Houston, TX 77005-1892,USA
Tel: 1-713-348-5355
Fax: 1-713-348-5353
E-mail: mikos@rice.edu

Johnna S. Temenoff
Department of Bioengineering, Rice University
6100 Main, MS 142, Houston, TX 77005-1892, USA
Tel: 1-713-348-5355
Fax: 1-713-348-5353
E-mail: temenoff@rice.edu

Departments of Bioengineering and Chemical Engineering,
Rice University, 6100 Main, Houston, TX 77005-1892


*Corresponding author

Financial Support: National Institutes of Health (USA, Grant nos. R01-AR44381, R01-DE13031, and R29-AR42639), Whitaker Foundation (USA)


Keywords: Bioresorbable materials, Poly(glycolic acid), Poly(lactic acid), Porogen, Porous foams, Tissue regeneration.

Despite recent technological advances, thousands die each year while waiting for organ transplants due to lack of donor organs or efficient organ substitutes (Thomson et al. 1995). Although clinicians have tried to replace the function of failing organs mechanically (dialysis and heart-lung bypass machines), or through implantation of synthetic replacements (blood vessel and joint replacements), these are often only temporary solutions and do not allow the patient to completely resume normal activities (Thomson et al. 1995). Infection and device rejection are also serious concerns in such procedures (Ishaug-Riley et al. 1997).

The emerging field of tissue engineering may help to resolve many of these problems. Tissue engineering involves the use of cells to regenerate the damaged tissue, leaving only natural substances to restore organ function. It has been found that in order for the cells to maintain their tissue-specific functions once implanted, a substrate material must be inserted to aid in organization of the cells in three dimensions (Temenoff et al. in press). In considering substrate materials, it is imperative to chose one that exhibits good biocompatibility. This means that the material must not be "rejected" by the immune system. In addition, the mechanical properties of the scaffold must be sufficient so that it does not collapse during the patient's normal activities. As with all materials in contact with the human body, these scaffolds must be easily sterilizable to prevent infection (Temenoff and Mikos in press).

Both natural and synthetic materials have been researched for use as tissue engineering scaffolds. Although preliminary results are promising for substrates derived from natural materials, such as collagen, (Wakitani et al. 1994; Caplan et al. 1997; Grande et al. 1997; Solchaga et al. 1999), concerns about the feasibility of finding the large amounts of material needed for clinical applications has prompted other researchers to investigate the use of synthetic polymers. These materials can be easily mass-produced and their properties can be tailored for specific applications. This includes creating degradable polymers that allow room for tissue growth in the construct while eliminating the need for a second surgery to remove the implant (Temenoff and Mikos 2000).

In particular, many investigators have concentrated on synthetic biodegradable polymers that are already approved by the U.S. FDA as suture materials. The most common of these polymers are poly(glycolic acid) (PGA), poly(L-lactic acid) (PLLA) and their copolymer, poly(DL-lactic-co-glycolic acid) (PLGA) (Thomson et al. 1995). These polymers offer distinct advantages in that their sterilizability and relative biocompatibility have been well documented. Also, their degradation rates can be tailored to match that of new tissue formation.

In addition to degradation rate, certain physical characteristics of the scaffolds must be considered when designing a substrate to be used in tissue engineering. In order to promote tissue growth, the scaffold must have large a large surface area to allow cell attachment. This is usually done by creating a highly porous polymer foam. In these foams, the pore size should be large enough so that cells penetrate the pores, and the pores must be interconnected to facilitate nutrient exchange by cells deep within the construct (Temenoff et al. in press). These characteristics (porosity and pore size) are often dependent on the method of scaffold fabrication (Mikos et al. 1993a; Mikos et al. 1994; Mooney et al. 1996a; Nam and Park 1999b; Nam et al. 2000).

Several methods have been developed to create highly porous scaffolds, including fiber bonding (Mikos et al. 1993a), solvent casting/particulate leaching (Mikos et al. 1993b; Mikos et al. 1994), gas foaming (Mooney et al. 1996a; Nam et al. 2000) and phase separation (Lo et al. 1995; Whang et al. 1995; Lo et al. 1996; Schugens et al. 1996; Nam and Park 1999a; Nam and Park 1999b). This review compares these methods in terms of foam porosity, pore size, efficacy of promoting tissue growth and ease of use in a clinical setting. Of these methods, fiber bonding, solvent casting/particulate leaching, gas foaming/particulate leaching and liquid-liquid phase separation produce large, interconnected pores to facilitate cell seeding and migration. The fiber bonding, solvent casting/particulate leaching and gas foaming/particulate leaching methods exhibit good biocompatibility, making these techniques especially promising for future use in tissue-engineered cell-polymer constructs. However, almost all techniques described in this review require the use of organic solvents, which could reduce the ability of cells to form new tissues in vivo. Thus, long processing times to fully remove these solvents are necessary. To overcome this problem, other combinations of materials and pore-forming techniques must be explored to create constructs that can be fabricated during surgery and tailored for specific applications. It is only when these clinical design criteria have been addressed that tissue engineered constructs will see widespread use to aid patients suffering from various types of organ and tissue failure.

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