Naturally occurring materials offer several advantages relative to synthetic materials, since the surrounding biological environment can recognize and metabolically process the substance through established pathways. Synthetic polymers can create toxicity, chronic inflammation, and clearance issues that are of less importance with natural materials. However, natural materials have historically been plagued with several drawbacks, including immunogenicity, lot-to-lot variability, and structural complexity, and inadequate biomechanical properties. Recent developments to reduce these unfavorable properties have led to a substantial number of successful biomaterials and biomaterial applications based on the unique properties of naturally occurring polymers and their chemically-modified derivatives.

A unique advantage to naturally derived materials is that through either enzymatic or hydrolytic degradation the host can successfully clear and metabolize the implanted substance. While this may not be desirable in permanent and long term implants such as hip replacements, it is extremely advantageous when timed biological resorption is desired, i.e., in delivery vehicles for drugs or therapeutic cells. Natural materials can be chemically modified and crosslinked to match the degradation rate to a particular biological application.

One frequent concern about natural materials is the immunogenic response that can occur following implantation. This response results from the fact that the implanted materials, although similar to endogenous host extracellular matrix component, may not be identical, and thus contain antigenic determinants. This issue is more common among protein based materials while typically significantly lower among polysaccharides iincluding glycosaminoglycans. Additionally, this immunogenic effect can be reduced by either chemical modification or through sourcing of the natural material. Chemical modification and crosslinking are common methods for altering mechanical properties such as elasticity and tensile strength of natural materials which are often not appropriate for dynamic physiologic environments (i.e. the beating myocardium.) However, the complex structures of natural materials can complicate technical modifications that are simple to perform in synthetic polymers. Nonetheless, numerous research studies have demonstrated the successful modification and purification of natural based materials. Another common issue arising with natural materials is the lot-to-lot variability in molecular structure that occurs due to animal sourcing. Variability arises not only due to species to species variation, but also from tissue to tissue variation. This can complicate processing and quantification of the materials. Recently bacterial recombinant techniques have been use to produce several natural materials including hyaluronic acid (HA) and collagen. This production technique reduces both the variability and immunogenicity issues with natural materials.