Polymer scaffolds are increasingly ubiquitous in the field of tissue engineering in improving the repair and regeneration of damaged tissue. Natural polymers exhibit better cellular adhesion and proliferation than biodegradable synthetics but exhibit inferior mechanical properties, among other disadvantages. Synthetic polymers are highly tunable but lack key binding motifs that are present in natural polymers. Using collagen and poly(lactic acid) (PLA) as models for natural and synthetic polymers, respectively, an evaluation of the cellular response of embryonic mouse fibroblasts (NIH 3T3 line) to the different polymer types was conducted. The samples were analyzed using LIVE/DEAD™, alamarBlue™, and phalloidin staining to compare cell proliferation on, interaction with, and adhesion to the scaffolds. The results indicated that NIH3T3 cells prefer collagen-based scaffolds. PLA samples had adhesion at the initial seeding but failed to sustain long-term adhesion, indicating an unsuitable microenvironment. Structural differences between collagen and PLA are responsible for this difference. Incorporating cellular binding mechanisms (i.e., peptide motifs) utilized by natural polymers into biodegradable synthetics offers a promising direction for biomaterials to become biomimetic by combining the advantages of synthetic and natural polymers while minimizing their disadvantages.