Table 1:

Potential advantages and disadvantages of strategies used to incorporate key biophysical properties of HA into biomaterial design.

Biophysical Property of HA in ECM	Strategy for Incorporating Property into HA Biomaterials	Potential Advantages and Disadvantages of Strategy
Mechanics
	Change HA density	Higher HA density increases both storage and loss modulus56,130,144 Higher density increases cell confinement and reduces spreading in 3D129,130,160
	Change molecular weight	HMW HA offers higher modulus, increased entanglement, and immunosuppressive signaling45,56,58,72 LMW HA offers low viscosities and can induce inflammation45,153
	HA backbone modification and crosslinking	Enables tunable control of crosslinking2,3,139,140 Can change viscosity depending on modification121,137 Can affect hydrophobicity of hydrogel167,170
	Incorporate interpenetrating / semi-interpenetrating networks	Network can be used to tune mechanical properties136,143 HA can interact with networking polymers128,159,161 May avoid HA backbone modification115,172
Adhesivity
Of HA backbone	HA backbone modification	Modification, especially of carboxylic acid and primary alcohol, reduces adhesivity of hyaladherins (cell receptors and ECM)150–152,154,155 Modifications can cause immunogenic response153
Of other ECM components	Peptide Conjugation	Requires backbone modification, which affects HA adhesivity
	Form Interpenetrating network with other ECM components	Networks may interact with HA backbone44,115,128,161
Degradability
Of HA backbone	Backbone modification	Backbone modification generally reduces degradability159,162–166
	Crosslinking	Crosslinker can affect degradability103,170
Of CrossIinkers	MMP-cleavable crosslinks	MMP cleavable linkages can enhance 3D cell spreading158 Relative role of hyaluronidases is unknown
	Crosslinks degrade by hydrolysis (i.e. esters)	Rates can be controlled by crosslinker type169,170 Native HA backbone is a product of hydrolysis allowing for hyaluronidase-based degradation169,170