Table 3.

Form-Factor Considerations in Achieving Compatible Sensor-Biology Interfaces^a

Issues	Importance	Challenges	Solutions and their limitations	Ref
Form-factor issues				33,49,529,532,580,581
Conformability	Signal quality	Intrinsic limitation of electronic materials	Ultrathin films including 2D materials: mechanical fragility, unstable interface to external circuits	386,390-392,460,555,582
	Motion artifacts	Microscale surface morphology	Soft, stretchable, viscoelastic, and adhesive polymers: limited performance and functionality, risk of irritation, difficult miniaturization	372,387-389,545,345-347,548,560,564,565
	Heat and mass transfer	Irregular and complex 3D shapes	Substrate structural engineering: complex manufacturing, added volume	583,584
		Dynamic surfaces	2D to 3D transformation: simple topography, tissue-incompatible processes Sol-gel materials: simple functionality	585-588 371,589
			Draw-on, print-on, and spray-on sensors: simple functionality, poor reproducibility	394,395,590-593
Permeability	Wearing comfort	Not a designed function of conventional sensors	Nanomeshes, 2D materials, and porous materials: mechanical fragility, unstable interface to external circuits	461,504,555,582,594-599
	Biocompatibility	Encapsulation
	Reliable adhesion	Whole-device permeability	Textiles (fibers, yarns, fabrics) and multifunctional integration: degradation upon washing, rigid processors and other modules impairing wearing comfort	32,103,600-606
	Long-term use		Ultrathin hydrogels: initial demonstrations only	607
Imperceptibility (Light weight, miniaturization, tissue-like mechanical properties, no tether)	Invasiveness	System-level imperceptibility	Ultrathin and mesh films including 2D materials: mechanical fragility, challenging system integration	56,57,309,390-392,582,596,608
	Comfort and convenience	Packaging volume	Fiber sensors: difficult handling unless integrated into textiles	600,609,610
	User compliance
Minimal invasiveness	Health risks	Skin barrier	Noninvasive deep-tissue sensing techniques: limited penetration depth, spatial resolution, temporal resolution, and wearability	390,566,611
	User acceptance	Deep-tissue signals	Microneedles: complex fabrication, low motion tolerance, ineffective passive sampling, difficult quantitative chemical sensing	612-619
		Biofluid sampling	Active biofluid induction: additional electrode and power supply, risk of irritation, concerns on drug intake	174,616
		Large device implantation	Injectable microsensors: difficult handling and connection, simple functionality	540,542
			Fiber sensors: small sensing area, difficult implantation, challenging system integration	127,544,620,621
			Contact lenses: small area, difficult integration	249,252,445,622,623
3D tissue coverage	Surface sensing on complex 3D structures	Minimal invasiveness	Self-expandable or multimodule microsensors: difficult handling and connection, simple functionality	540,542,624
	Interior sensing of bulk tissues	Precise positioning
	Volumetric mapping	Spatial resolution	Cell seeding on electronic scaffolds: inapplicable to grown tissues	625
		End-of-life withdrawal/degradation	Developmental biology-driven 3D assembly: inapplicable to grown tissues, cell-type limitation	527,543,626
		Immune response	Mechanics-guided 3D assembly: complex inverse design, challenging micro/nano-scale fabrication	627-630

^aTheir importance, specific challenges, reported solutions to these challenges, and limitations of the solutions are listed briefly.