Introduction:
Silk fibroin (SF) lyogels are promising biomaterials for tissue engineering and drug delivery; however, their performance is strongly influenced by pore architecture and degradation behavior. Understanding how processing routes affect these properties is essential for designing application-specific systems.

Methods:
Lyogels were prepared from regenerated aqueous SF derived from Bombyx mori silk using two gelation approaches: storage-induced self-agglomeration (5% w/v) and ultrasonication (7% w/v). The gels were subsequently freeze-dried to obtain porous lyogels. The materials were characterized for pore morphology, swelling kinetics, hydrophilicity, in vitro enzymatic degradation (Protease XIV, 1 U/mL), and drug release behavior.

Results:
Self-agglomerated lyogels exhibited smaller and more uniform pores, slower swelling, and prolonged structural integrity. In contrast, ultrasonicated lyogels showed larger, more heterogeneous pores and rapid water uptake, absorbing up to ~1800% of their dry weight within 1 h, whereas self-agglomerated lyogels absorbed less than 1000% but continued swelling for over one week. Under enzymatic conditions, ultrasonicated lyogels degraded completely within 48–72 h, while self-agglomerated lyogels retained their structure beyond 4 days. Drug release studies indicated faster release from ultrasonicated lyogels (T₅₀% ≈ 0.68 h) compared to self-agglomerated lyogels (T₅₀% ≈ 1.03 h).

Conclusions:
These findings demonstrate that modulation of SF gelation provides an effective strategy to tailor pore structure, swelling behavior, degradation rate, and drug release kinetics. This enables the rational design of lyogels for burst or sustained drug delivery and tissue engineering applications.