Developmental aspects of the tympanic membrane: Shedding light on function and disease

Abstract

The ear drum, or tympanic membrane (TM), is a key component in the intricate relay that transmits air-borne sound to our fluid-filled inner ear. Despite early belief that the mammalian ear drum evolved as a transformation of a reptilian drum, newer fossil data suggests a parallel and independent evolution of this structure in mammals. The term "drum" belies what is in fact a complex three-dimensional structure formed from multiple embryonic cell lineages. Intriguingly, disease affects the ear drum differently in its different parts, with the superior and posterior parts being much more frequently affected. This suggests a key role for the developmental details of TM formation in its final form and function, both in homeostasis and regeneration. Here we review recent studies in rodent models and humans that are beginning to address large knowledge gaps in TM cell dynamics from a developmental biologist's point of view. We outline the biological and clinical uncertainties that remain, with a view to guiding the indispensable contribution that developmental biology will be able to make to better understanding the TM.

Keywords: development; middle ear; tympanic membrane.

Figure 1

Middle ear anatomy. (a) Schematic of a sauropsid (e.g., bird or lizard) showing a single columella (or stapes) in the middle ear cavity. (b) Schematic of a mammalian middle ear showing a three‐ossicular chain connecting the tympanic membrane to the cochlea. EAC, external auditory canal; ET, eustachian tube; I, incus; IE, inner ear; M, malleus; MEC, middle ear cavity; S, stapes; TM, tympanic membrane

Figure 2

Tympanic membrane structure. (a) A murine tympanic membrane. The pars flaccida is broader and larger in comparison to (b) the triangular shaped pars flaccida of the human tympanic membrane. Asterisks denote areas of the eardrum most commonly affected by disease such as cholesteatoma or nonhealing perforations. (c) Schematic of human tympanic membrane. The pars flaccida and pars tensa are separated by the malleolar folds. The manubrium of the malleus inserts into and abuts the pars tensa. (d) and (e) Trichrome and schematic cross sections along dotted red line in (c) showing the three layers of the tympanic membrane with the pars flaccida being thicker than the pars tensa. MF, malleolar fold; MM, manubrium of malleus; PF, pars flaccida; PT, pars tensa

Figure 3

Cell dynamics in the outer epidermal layer of the tympanic membrane. (a) Location and movement of stem/progenitor cells based on lineage tracing experiments and proliferation assays (Frumm et al., 2019; Knutsson, von Unge, & Rask‐Andersen, 2011). (b) Migration patterns of keratinocytes based on ink dye labeling experiments in rodents and humans (Jackler, Santa Maria, Varsak, Nguyen, & Blevins, 2015; Michaels & Soucek, 1991). There is some variation in the reported pattern in humans (Alberti, 1964)

Figure 4

Example of a finite element model of a tympanic membrane (plus the malleus and its anterior ligament). A geometric mesh is used to model TM properties such as stiffness, allowing for predictive insights into how the TM may behave in response to sound waves. (Reprinted from Lobato, Paul, & Julio, 2018 with permission from AIP Publishing)

Figure 5

Development of the tympanic membrane. (a) and (b) Cells from the region of the first cleft invaginate toward the first pouch meanwhile the ossicles form within the neural crest cell derived mesenchyme. (c) The developing ectoderm‐derived ear canal and endoderm‐derived middle ear cavity sandwich a layer of mesenchyme between them forming a three‐layered tympanic membrane. (Modified and reprinted from Mallo, 2001 with permission from Elsevier). EAM, external auditory meatus; I, incus; IE, inner ear; M, malleus; MEC, middle ear cavity; MM, malleus manubrium; OW, oval window; SA, stapedius arm; SF, stapedius footplate; TB, temporal bone; TM, tympanic membrane