RARE DISEASE
Microtia
Microtia
Microtia
Drug discovery
2
drugs
With orphan designations
Overview
Microtia is a congenital malformation of the external ear, ranging from minor structural anomalies to complete absence (anotia), often associated with ear canal atresia and conductive hearing loss. It occurs in 1–5 per 10,000 births, with higher prevalence in males and specific ethnic groups. Diagnosis is clinical, supported by CT imaging for middle ear assessment. Management involves multidisciplinary care, addressing hearing rehabilitation and surgical reconstruction using autologous cartilage or synthetic implants, typically initiated between ages 5–10.
Population
Prevalence: 1–5 per 10,000 births globally, with elevated rates in Hispanic, Asian, Native American, and Andean populations [2][7][15].
Demographics: 90% unilateral (right ear predominance); male-to-female ratio 2:1 [1][6][15].
Syndromic associations: Present in 4–10% of cases (e.g., hemifacial microsomia, Treacher Collins) [10][12][18].
Burden
Functional: Conductive hearing loss in 80–90% of cases, impacting speech development without intervention [6][18].
Psychosocial: Increased risk of bullying, body image concerns, and anxiety, particularly post-age 6 [1][6][12].
Surgical: Complications include cartilage resorption (9–32%), infection, and scar contracture, often requiring revision [8][16].
Therapies
Reconstructive surgery: Autologous rib cartilage grafting (4-stage Nagata/Brent techniques) remains gold standard [1][8][16]; Medpor® implants enable earlier single-stage reconstruction [3][16].
Prosthetics: Silicone options for nonsurgical management, requiring adhesive/magnetic attachment [6][12].
Hearing rehabilitation: Bone-anchored hearing aids (BAHA) or canaloplasty for atresia [10][12][18].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare otorhinolaryngological diseases
Research Papers
1,397 drug discovery papers about Microtia, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
1,397 drug discovery papers about Microtia, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-09-17 | Evolution and Hotspots in Autologous Ear Reconstruction: A Bibliometric Analysis of the 100 Most-cited Studies.
Autologous auricular reconstruction has evolved from cartilage-carving techniques that established modern microtia repair to an expanding regenerative and biofabrication literature. However, the field has not been mapped bibliometrically using an autologous-only lens that separates the clinical literature from emerging tissue-engineering hotspots. A Scopus search in January 2026 identified publications on autologous auricular reconstruction. Records were sorted by citation count, screened for eligibility, and the 100 most-cited studies were included. Data extracted included citations, citations per year, year, journal, country, and evidence category. Studies were classified into 4 domains: surgical technique, tissue engineering/basic science, complications/management, and outcomes/quality of life. VOSviewer was used for coauthorship and keyword co-occurrence mapping. Temporal shifts were assessed by comparing the older versus newer halves. The 100 most-cited studies (1971-2023) accrued a mean of 82.97 citations (range, 27-510) with a median of 3.46 citations per year. Most studies were clinical (71%), followed by preclinical (19%) and evidence synthesis (10%). Surgical technique predominated overall (53%), but decreased from 66% in the older half to 40% in the newer half, whereas tissue engineering increased from 16% to 28%. The most-cited article was the description by Nagata of a 2-stage, 3-dimensional costal cartilage framework (1993, Plastic and Reconstructive Surgery). Keyword clustering revealed a temporally newer regenerative cluster centered on chondrocytes, tissue engineering, and biomechanics. The citation canon of autologous auricular reconstruction is built on the late 20th-century technique classics, whereas contemporary influence is increasingly driven by regenerative medicine and biofabrication. Future high-impact work will likely be defined by durable, shape-stable engineered constructs validated in clinically relevant models.
2026-09-16 | Auricular cartilage tissue engineering: from making cartilage to regenerating a shape-stable elastic organ.
Auricular cartilage tissue engineering has long been grouped under the broader category of craniofacial cartilage reconstruction, but this classification is becoming insufficient. Unlike articular cartilage repair, which mainly aims to restore load-bearing function and relieve pain, auricular reconstruction must reproduce a complex three-dimensional structure, preserve elastic recoil, resist long-term contraction, tolerate soft-tissue coverage, and remain surgically and aesthetically acceptable over time. These demands make auricular cartilage engineering fundamentally distinct from generic cartilage engineering. Over the past decade, the field has progressed from proof-of-concept ear-shaped constructs in small-animal models to more advanced strategies, including patient-specific scaffold design, expansion of autologous auricular chondrocytes, coculture systems, decellularized auricular extracellular matrices, and 3D printing or bioprinting. Together, these advances indicate that auricular cartilage tissue engineering has moved beyond simple proof-of-concept. However, routine clinical translation remains constrained by unresolved challenges, including long-term shape maintenance, soft-tissue coverage, inflammatory remodeling, scaffold degradation, reproducible manufacturing, regulatory approval, and integration into pediatric reconstructive workflows. At the same time, they reveal a key conceptual limitation: many studies still define success as the formation of "cartilage-like" tissue, even though auricular regeneration ultimately requires a stable elastic organ rather than a histologically acceptable cartilage mass. In this perspective, we argue that the field has reached a stage where conceptual refinement is as important as technical innovation. Future progress, we propose, depends on three related shifts: moving from a generic chondrogenic paradigm to one centered on elastic cartilage biology; redefining scaffolds as instructive microenvironments rather than mere shape-retaining supports; and evaluating translational success not only by feasibility, but also by reproducibility, manufacturability, and long-term clinical robustness. Rather than offering another technique-centered review of auricular reconstruction, this Perspective advances an auricular-specific framework for defining success in elastic organ regeneration. The next major advances, in our view, will come from approaches that integrate elastic cartilage biology, instructive scaffold design, and measurable translational criteria rather than optimizing these dimensions separately.
2026-09-09 | A Ten-Year Retrospective Cohort Study on Auricular Reconstruction: Comparative Analysis of Three Surgical Techniques.
Microtia significantly impacts patients' quality of life due to physical, financial, and psychological burdens. Auricular reconstruction, the main treatment for microtia, is considered a significant challenge, given its high demand, complex nature, and need for meticulous precision. This study conducted a retrospective analysis of three widely used techniques for auricular reconstruction within our clinical practice over a 10-year period, providing substantial comparative insights and experiences into the customization of auricular reconstruction. From January 2015 to January 2025, our center performed auricular reconstruction on 1677 microtia patients. Of these, 1582 completed follow-up and joined the study. In the patient cohort, 402 received the modified two-step method, 462 had the expanded two-flap technique, and 718 underwent the single-expanded flap procedure. The cumulative operative time, total length of postoperative hospital stays, duration of therapy, and incidence of postoperative complications across all surgical stages within three distinct groups were analyzed. Additionally, patients' satisfaction with surgical outcomes was assessed. The patients were followed up for between 6 months and 10 years. The single-expanded flap technique achieved the highest satisfaction score. The modified two-step method group demonstrated the shortest cumulative operative time, and duration of therapy. The benefits, limitations, and distinct attributes of each method's application were subsequently examined and synthesized. Auricles reconstructed using the single-expanded flap technique exhibit minimal scarring, uniform color, and greater patient satisfaction. However, no single approach can be universally suitable for every patient. Thorough preoperative assessments and careful selection of indications ultimately yield positive outcomes in auricle reconstruction procedures. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
2026-09-01 | "Bio-Hammock" technique for prevention of expander inferior displacement in auricular reconstruction: A retrospective comparative cohort study of 198 patients.
Inferior displacement of tissue expanders during first-stage auricular reconstruction remains a persistent clinical challenge. We evaluated a modified dual-plane "bio-hammock" technique, in which the inferior pole of the expander (approximately 1.5-2.0 cm) is embedded within an intramuscular pocket fashioned within the sternocleidomastoid muscle (SCM) belly, because of its efficacy in preventing inferior displacement and reducing complications. A retrospective cohort study was conducted on 198 patients with unilateral microtia who underwent first-stage expander implantation between January 2022 and December 2025. The modified dual-plane cohort (n=99) was treated using the modified dual-plane technique and conventional single-plane cohort (n=99) was treated using the conventional single-plane technique. All expanders (80 ml) were over-inflated to approximately 110 ml (137.5% of nominal volume). The primary outcome was inferior displacement distance prior to the second-stage procedure and secondary outcomes included complication rates, VAS pain scores, and patient satisfaction. Inferior displacement was significantly reduced in the modified dual-plane cohort compared with the conventional single-plane cohort [median 0.30 (IQR: 0.22-0.38) cm vs. 1.40 (IQR: 1.15-1.70) cm; P<0.001], representing a 78.6% reduction. The overall complication rate was 2.0% vs. 7.1% (P=0.170), with zero expander exposure in the modified dual-plane cohort vs. 4.0% in the conventional single-plane cohort (P=0.121). Early postoperative VAS scores were marginally higher in the modified dual-plane cohort; however, they normalized by postoperative day 7. The "bio-hammock" technique provides superior mechanical stability against gravitational inferior displacement under extreme over-inflation conditions, with a favorable safety profile including zero expander exposure. This technique represents a safe and effective refinement for first-stage auricular reconstruction.
2026-07-06 | Engineering the Auricular Cartilage by Hydrogel‐ and Microgel‐Based 3D Bioprinted Constructs—An Update
ABSTRACT Auricular cartilage defects, resulting from congenital malformations such as microtia or acquired causes including trauma, infections, and tumor resection, significantly impair facial symmetry, auditory function, and psychosocial well‐being. Conventional reconstruction methods, such as autologous costal cartilage grafting and alloplastic implants, have limitations, including donor‐site morbidity, infection risk, calcification, immune rejection, and an inability to replicate the auricle's complex architecture and elastic biomechanics. To address these challenges, researchers have developed biomaterial‐based scaffolds that offer high tissue compatibility, precise shape fidelity, and minimally invasive delivery. In this regard, three‐dimensional (3D) bioprinting has emerged as a transformative technology, enabling the fabrication of patient‐specific constructs with controlled spatial deposition of biomaterials, bioactive molecules, and living cells, thereby facilitating the generation of functional auricular cartilage. This review presents the essential design criteria for bioinks tailored to auricular cartilage bioprinting, encompassing cell sourcing strategies, rheological properties and printability, bioactive factor incorporation, and mechanical performance. It then overviews recent advances in hydrogel‐ and microgel‐based bioinks for 3D and four‐dimensional (4D) bioprinting of patient‐specific auricular constructs, emphasizing natural, synthetic, and hybrid hydrogel systems. Finally, the review discusses current material and technological limitations and outlines prospective research directions to guide future studies and accelerate innovations in auricular cartilage regeneration.
small molecules
2026-06-01 | Management of Acute Postoperative Infections Following Microtia Reconstruction With Costal Cartilage Grafts.
Acute postoperative infection is a serious complication of microtia. This study analyzes infection rates and treatment outcomes to identify risk factors and improve infection control strategies. We reviewed data from June 2014 to May 2024 for 630 ears (577 patients) that underwent costal cartilage grafting and 573 ears (527 patients) that underwent ear elevation. The primary endpoint was infection onset within 1 month after surgery and clinical outcome. Secondary endpoints included remnant cartilage classification, hairline position, case type (primary versus secondary cases), medical history and comorbidities, operative time, length of hospital stay, hematoma or local wound complications, and the method of cartilage framework fixation. In addition, the timing, causative organisms, and management of infections were investigated. Infection and cartilage framework removal rates were significantly higher in the costal cartilage grafting group. Univariate and multivariate analyses revealed that hematoma, secondary cases, and local wound complications were independent risk factors for postoperative infection in the costal cartilage grafting group. Early aggressive irrigation and debridement allowed preservation of the cartilage framework, and approximately 58% of these cases maintained an auricular contour comparable to that before infection. Hematoma, secondary cases, and local wound complications were independent risk factors for acute infection after costal cartilage grafting. Surgical procedures focusing on hematoma prevention and adequate flap perfusion are important to reduce infection risk. Early surgical intervention with systemic antibiotics in the initial phase of infection may help preserve the grafted cartilage and achieve successful auricular reconstruction.
2026-02-13 | Clinical Salvage Approaches for Surgical Site Infection After Autologous Microtia Reconstruction.
Background/Objectives: Surgical site infection (SSI) after autologous rib cartilage microtia reconstruction is an uncommon but potentially devastating complication, as infection of the avascular cartilage framework can rapidly lead to partial or complete framework loss. Traditional management often favored aggressive debridement or framework removal, resulting in significant deformity. This study aimed to evaluate salvage-oriented management strategies and to propose a structured treatment algorithm for SSI following microtia reconstruction. Methods: A retrospective case series was conducted of patients who developed SSI after autologous rib cartilage microtia reconstruction between March 2021 and November 2025. SSI was defined by clinical and surveillance criteria requiring intervention beyond routine postoperative care. Nine patients were included. Management strategies were analyzed with respect to infection control, framework preservation, and wound healing outcomes. Results: SSI occurred at variable time points, ranging from early postoperative infection to delayed and late-onset presentations. Identified pathogens included Gram-positive cocci and multidrug-resistant Gram-negative organisms. Negative-pressure wound therapy (NPWT) was applied in all cases with wound dehiscence, persistent drainage, or cartilage exposure. Conservative staged debridement was performed only after clear demarcation of nonviable tissue. Overall auricular framework preservation was achieved in 100% of patients, with no cases requiring complete framework removal, although limited cartilage loss occurred in select cases. These outcomes demonstrate the clinical feasibility and effectiveness of salvage-oriented management across heterogeneous infection scenarios. Conclusions: SSI following autologous microtia reconstruction can be effectively salvaged without routine framework removal through a structured, timing-based algorithm emphasizing early culture-guided antimicrobial therapy, NPWT, and conservative staged intervention. This salvage-oriented approach provides a clinically relevant and reproducible framework for preserving auricular structure while minimizing morbidity, even in infections involving multidrug-resistant organisms.
2025-12-27 | CRABP2 Upregulation in Perichondral Stem Cells is Associated with Microtia
Abstract Microtia is a common congenital craniofacial malformation characterized by the partial or complete absence of the external ear structure. Despite its relatively high incidence, the pathogenesis of microtia remain poorly understood. In this study, we analyzed both single-cell and bulk RNA sequencing data from microtia cases and identified a population of COL1 + HES1 + mesenchymal stem cell in perichondrium with significantly higher expression of the CRABP2 gene, a gene that encodes a nuclear transporter of retinoic acid. Gene expression analysis further confirmed that the RA signaling intensity and stemness are both higher in COL1 + HES1 + perichondral stem cells from microtia patients, possibly due to elevated CRABP2 levels. Through histological verification we further confirmed the presence of this cell population with high CRABP2 expression in the perichondrium. Mechanistically, the elevated CRABP2 expression in perichondral stem cells seen in microtia patients may cause dysregulated RA signaling and disrupt the regulation of stem cell differentiation during auricular development. Histological analysis further revealed higher KLF2 expression as well as cartilage hypoplasia in microtia samples. Our study identified that the CRABP2-induced RA dysregulation in COL1 + HES1 + perichondral stem cells may contribute to microtia. These findings offer new insights into the etiology of microtia and provide potential directions for prenatal prevention and tissue engineering treatments.
2024-09-30 | Abdominal muscles infiltration analgesia for donor-site pain in autologous ear reconstruction: A randomized controlled clinical trial.
Costal cartilage donor-site pain is an adverse effect of autologous ear reconstruction. This study aimed to introduce rectus abdominis and external oblique muscle infiltration analgesia (RAM+EOM-IA) for costal cartilage donor-site pain and evaluate its efficacy and safety. The study was a randomized controlled clinical trial. Patients were randomized between intermittent RAM+EOM-IA combined with intravenous patient-controlled anesthesia (IPCA) and IPCA alone. Thirty patients were followed in the RAM+EOM-IA combined with the IPCA group and 30 patients in the IPCA alone group. The primary outcome was the numerical rating score (NRS) of pain recorded during 48 h postoperatively. Secondary outcomes included the Barthel index (BI) and rescue analgesic consumption. Sensory block areas were tested using a cold stimulus. NRS was significantly lower with RAM+EOM-IA combined with IPCA than with IPCA alone at 28 h (P < 0.01), 32 h (P < 0.01), 36 h (P < 0.01), 44 h (P < 0.001), and 48 h (P < 0.01) postoperatively. The number of patients who received rescue analgesics (P < 0.01) and consumption (P < 0.01) was significantly higher for IPCA alone. RAM+EOM-IA improved the BI at 24 h postoperatively (P < 0.001), especially for mobility (P < 0.001), using the stairs (P < 0.001) and toilet use domains (P < 0.001). At 10 and 60 min after RAM+EOM-IA, the total sensory block area in the abdomen had not extended proximally beyond the xiphoid, distally beyond the navel, and beyond midaxillary and midsternal lines on either side. RAM+EOM-IA effectively and safely prevented costal cartilage donor-site pain by blocking anterior and lateral cutaneous branches of intercostal nerves from T6 to T10 in microtia patients.
2024-06-05 | Decreased Tiam1-mediated Rac1 activation is responsible for impaired directional persistence of chondrocyte migration in microtia.
The human auricle has a complex structure, and microtia is a congenital malformation characterized by decreased size and loss of elaborate structure in the affected ear with a high incidence. Our previous studies suggest that inadequate cell migration is the primary cytological basis for the pathogenesis of microtia, however, the underlying mechanism is unclear. Here, we further demonstrate that microtia chondrocytes show a decreased directional persistence during cell migration. Directional persistence can define a leading edge associated with oriented movement, and any mistakes would affect cell function and tissue morphology. By the screening of motility-related genes and subsequent confirmations, active Rac1 (Rac1-GTP) is identified to be critical for the impaired directional persistence of microtia chondrocytes migration. Moreover, Rho guanine nucleotide exchange factors (GEFs) and Rho GTPase-activating proteins (GAPs) are detected, and overexpression of Tiam1 significantly upregulates the level of Rac1-GTP and improves directional migration in microtia chondrocytes. Consistently, decreased expression patterns of Tiam1 and active Rac1 are found in microtia mouse models, Bmp5se/J and Prkralear-3J/GrsrJ. Collectively, our results provide new insights into microtia development and therapeutic strategies of tissue engineering for microtia patients.
proteins
2026-06-10 | Modern methods of cartilaginous microtia reconstruction.
The purpose of this manuscript is to review current literature of modern cartilaginous microtia reconstruction techniques and describe evolving biotechnological advancements within this field. We additionally offer opinions on technical refinements from our institutional experience with autologous rib cartilage reconstruction performed for nearly 30 years. Autologous rib cartilage reconstruction is the gold standard for microtia treatment. There is active research in developing alternative framework materials, including allogenic and tissue-engineered cartilage. Advancements in technology such as three-dimensional bioprinting play an increasing role in the personalization and precision of auricular reconstruction. Microtia reconstructive surgery presents a challenge in balancing aesthetic goals with minimal morbidity. Cartilage offers framework strength as well as pliability for custom shaping. Tissue-engineered cartilage for microtia is promising, prompting research in this field focused on elucidating long-term durability and safety. A robust understanding of cartilaginous options for auricular reconstruction in the context of modern evidence and technology can improve both patient and surgeon satisfaction.
2026-02-06 | Analysis of Eya1 and Tbx1 mutants highlights interactions between the muscle and developing cartilage during external ear formation.
Microtia is a common feature of several human syndromes affecting the external ear (pinna), yet the cellular and molecular mechanisms remain poorly understood. Using human embryos and mouse models of branchio-oto-renal (BOR) and 22q11.2 deletion syndromes, we show that the syndromic genes Eya1 and Tbx1 are expressed in mesoderm-derived auricular muscle. In Eya1 mutant mice, auricular muscles failed to form and pinna morphogenesis was disrupted, with comparable defects observed in mesoderm-specific Tbx1 mutants. Both mutant pinnae exhibited impaired cartilage differentiation, suggesting that auricular muscle provides signals to the neural crest-derived mesenchyme to regulate cartilage differentiation. In contrast, defects in cartilage development alone or loss of muscle contraction did not affect early pinna morphogenesis. Auricular myocytes expressed Fgfs, while the surrounding mesenchyme expressed Fgfr1, Fgfr2 and ERM proteins. Disrupted Fgf signalling was observed in mutant cartilage and muscle. In ex vivo cultures, inhibition of Fgf or Bmp signalling recapitulated cartilage defects, whereas BMP4 restored Sox9 expression. These findings identify the mesoderm as essential for pinna initiation and morphogenesis, and reveal signalling mechanisms underlying microtia in BOR and 22q11.2 deletion syndromes.
2024-12-17 | Lactoferrin Stimulates Chondrogenesis and Promotes Healing of the Auricular Elastic Cartilage
Ear reconstruction surgeries, including those addressing congenital deformities like microtia and trauma-induced damages, are relatively common. Given the demand, seeking new approaches to cartilage regeneration is crucial to improving surgical outcomes, reducing recovery times, and enhancing the quality of life for patients. The natural and cost-effective protein lactoferrin (LF) draws significant attention. It is renowned for its anti-inflammatory, antimicrobial properties, and its ability to stimulate chondrogenesis of the hyaline cartilage. This study investigates the effects of LF on the viability, proliferation, and chondrogenesis of rabbit auricular chondrocytes using both in vitro and in vivo models. In vitro, LF significantly increased the metabolic activity of chondrocytes in a dose-dependent manner, with an optimal concentration of 10 μg/ml enhancing cell prolifera-tion and metabolic activity. At this concentration, it also stimulated chondrogenesis. For in vivo studies, a rabbit ear defect model was used. Macroscopic and histological analyses revealed that LF-treated groups exhibited more mature cartilage regeneration, with higher density and organi-zation of elastic fibers compared to control. These findings suggest that LF promotes auricular chondrocyte chondrogenesis and could be beneficial for tissue engineering and clinical applications in cartilage repair.
2024-03-06 | A Case of Parotid Gland Fistula After Microtia Reconstruction Successfully Treated With Botulinum Toxin Type A.
Parotid gland fistula after microtia reconstruction is relatively rare, with only 3 cases having been reported in the literature. It may be caused by the presence of an accessory parotid gland or surgical damage to parotid gland tissues. The principal treatment is dressing the wound. Here, we report the first case of parotid fistula after microtia reconstruction using a delayed retroauricular flap, which healed following wound dressing and an injection of botulinum toxin type A (CBTXA) into the parotid gland.
2023-11-22 | BMP9 is a potent inducer of chondrogenesis, volumetric expansion and collagen type II accumulation in bovine auricular cartilage chondroprogenitors
Reconstruction of the outer ear currently requires harvesting of cartilage from the posterior of the auricle or ribs leading to pain and donor site morbidity. An alternative source for auricular reconstruction is in vitro tissue engineered cartilage using stem/progenitor cells. Several candidate cell-types have been studied with tissue-specific auricular cartilage progenitor cells (AuCPC) of particular interest. Whilst chondrogenic differentiation of competent stem cells using growth factor TGFβ1 produces cartilage this tissue is frequently fibrocartilaginous and lacks the morphological features of hyaline cartilage. Recent work has shown that growth factor BMP9 is a potent chondrogenic and morphogenetic factor for articular cartilage progenitor cells, and we hypothesised that this property extends to cartilage-derived progenitors from other tissues. In this study we show monoclonal populations of AuCPCs from immature and mature bovine cartilage cultured with BMP9 produced cartilage pellets have 3-5-fold greater surface area in sections than those grown with TGFβ1. Increased volumetric growth using BMP9 was due to greater sGAG deposition in immature pellets and significantly greater collagen accumulation in both immature and mature progenitor pellets. Polarised light microscopy and immunohistochemical analyses revealed that the organisation of collagen fibrils within pellets is an important factor in the growth of pellets. Additionally, chondrocytes in BMP9 stimulated cell pellets had larger lacunae and were more evenly dispersed throughout the extracellular matrix. Interestingly, BMP9 tended to normalise the response of immature AuCPC monoclonal cell lines to differentiation cues whereas cells exhibited more variation under TGFβ1. In conclusion, BMP9 appears to be a potent inducer of chondrogenesis and volumetric growth for AuCPCs a property that can be exploited for tissue engineering strategies for reconstructive surgery though with the caveat of negligible elastin production following 21-day treatment with either growth factor.
gene therapies
2026-09-26 | Relationship Between External Ear Severity and Temporal Bone Malformation in Microtia: A Computed Tomography Study.
Background/Objectives: Microtia is frequently associated with temporal bone malformations, but the extent to which external ear phenotype reflects underlying CT-defined anatomy remains uncertain. This study aimed to compare the relationships of Marx severity grading and Nagata morphological classification with temporal bone anatomy in patients with microtia. Methods: This retrospective study included 26 patients with 27 affected ears who had both preoperative external ear photographs and temporal bone computed tomography (CT) examinations. Each affected ear was classified according to the Marx and Nagata systems, and temporal bone anatomy was assessed using the modified Jahrsdoerfer CT scoring system. Associations were evaluated using Spearman rank correlation and permutation-based Jonckheere-Terpstra analysis, with an additional patient-level sensitivity analysis. Results: Considerable variation in Jahrsdoerfer scores was observed within external ear phenotypic categories, with substantial overlap between Marx Grades II and III and lower scores concentrated in Grade IV. The inverse association between Marx grade and Jahrsdoerfer score did not reach conventional statistical significance (ρ = -0.380, p = 0.051), whereas the Jonckheere-Terpstra test identified an overall decreasing trend (permutation p = 0.025). This trend no longer reached statistical significance in the patient-level sensitivity analysis. Nagata classification did not significantly discriminate CT-based radiological severity. Conclusions: Greater external auricular severity may be associated with less favorable temporal bone anatomy, but the relationship was not uniform across successive Marx grades. Marx and Nagata classifications provide complementary phenotypic information, but neither consistently reflected the extent of underlying temporal bone malformation. These preliminary findings emphasize phenotype-CT variability and support individualized CT-based anatomical assessment when imaging is clinically indicated.
2026-04-09 | Genetic variation near ROBO1 is associated with craniofacial microsomia and related phenotypes in the Finnish population.
Craniofacial microsomia (CFM) encompasses a phenotypic continuum of congenital anomalies ranging from isolated microtia to more complex manifestations within the oculo-auriculo-vertebral spectrum, including Goldenhar syndrome, reflecting abnormal development of first and second pharyngeal arch-derived structures. While several genetic susceptibility loci have been reported, population-based evidence in individuals of European ancestry remains limited. Using nationwide data from FinnGen in the Finnish founder population, we identified a genome-wide significant association at a conserved intergenic locus near ROBO1, extending previous findings to a European ancestry cohort. The lead variant, rs62256696, lies within a regulatory region active in human embryonic craniofacial tissues during early development and shows concordant association with previously reported ROBO1 signals from non-European populations. Genetic correlation analyses demonstrated strong shared genetic architecture between CFM and auditory developmental phenotypes, consistent with the defined phenotypic continuum. Together, these findings extend previous observations to a new population context and support a role for regulatory variation at the ROBO1 locus in early craniofacial morphogenesis and auditory system development underlying craniofacial and auditory malformations.
2025-12-31 | The Microtia in Treacher Collins Syndrome
Introduction: Treacher Collins Syndrome (TCS) is a condition affecting the development of facial structures. TCS presents with variable clinical manifestations and can impact the quality of life of those affected. Early identification and diagnosis are crucial management planning and intervention. Objective: To understand the embryology, genetic abnormalities, and manifestations of TCS which would facilitate the diagnosis. Methods: A narrative review of the literature published between 2010 and 2024. The literature search was conducted using the keywords "Treacher Collins Syndrome" and related terms (embryology, epidemiology, diagnosis) across academic databases such as PubMed, Google Scholar, and ScienceDirect. Result: From the 116 articles identified, a review was conducted on 23 publications deemed relevant and appropriate to the topic. Treacher Collins Syndrome (TCS), also known as Mandibulofacial Dysostosis, is a genetic disorder affecting facial structures, characterized by variable clinical manifestations. TCS has impact on the quality of life of those affected. It is inherited in an autosomal dominant manner and involves mutations in the TCOF1, POLR1D, POLR1C or POLR1B genes, which disrupts the development of the pharyngeal arches during embryogenesis. Microtia and conductive hearing loss are otology manifestations of TCS. TCS is diagnosed based on clinical manifestations, along with genetic confirmation. Conclusion: Identification and diagnosis of Treacher Collins Syndrome (TCS) are crucial for planning management and interventions that can improve the patient's quality of life.
2025-01-28 | Epidemiological Characteristics and Maternal Risk Factors of Microtia and Aural Atresia in Kazakhstan.
Introduction Microtia and aural atresia present congenital ear anomalies that affect external ear and are associated with conductive hearing loss. Both anomalies result from exposure to various prenatal risk factors, most common during the first trimester of pregnancy. Objective This study was aimed at epidemiological analysis of microtia/atresia and associated risk factors in the Kazakhstani population. Methods A retrospective study in two stages. First, a cross-sectional analysis of microtia/ atresia frequencies from 2015 to 2019 on the basis of official statistics obtained from the Republican Centre for E-Health. Then, a case-control study was carried out to elucidate maternal risk factors associated with occurrence of microtia/atresia. We recruited patients presented in Almaty, Kazakhstan, between September 2021 and February 2022. Results There was a substantial regional variation in the rates of both aural atresia and microtia/anotia. Mothers of children with microtia disclosed toxoplasmosis, other agents (including HIV, syphilis, varicella), rubella, cytomegalovirus, herpes simplex (TORCH) infections during pregnancy more often than those of healthy children (45.8 versus 7.3%; p < 0.001). Exposure to different chemicals during pregnancy was mentioned more frequently by mothers of children with microtia when compared with the healthy controls (18.1 versus 8.1%; p = 0.035). Self-reporting of alcohol consumption and intake of antibiotics was also significantly higher in mothers of children with microtia (31.9 and 36.1% respectively). Conclusion Elucidation of microtia/atresia epidemiology is important due to their imposed social and economic burden, associated with treatment and rehabilitation costs.
2025-01-02 | Double network hydrogels encapsulating genetically modified dedifferentiated chondrocytes for auricular cartilage regeneration.
Microtia profoundly affects patients' appearance and psychological well-being. Tissue engineering ear cartilage scaffolds have emerged as the most promising solution for ear reconstruction. However, constructing tissue engineering ear cartilage scaffolds requires multiple passaging of chondrocytes, resulting in their dedifferentiation and loss of their special phenotypes and functions. To tackle these issues, here we employ guanidinobenzoic acid (GBA) modified generation 5 polyamidoamine (PAMAM) dendrimers (PG) as a Runx1 plasmid carrier to construct PG/pRunx1 polyplex nanoparticles. The PG/pRunx1 polyplexes are transfected into human auricular chondrocytes, significantly mitigating chondrocyte dedifferentiation and enhancing cartilage regeneration during the in vitro culture. Furthermore, we develop highly porous double-network hydrogels based on methacrylate-functionalized and oxidized chondroitin sulfate and carbohydrazide-modified gelatin and the hydrogels possessed both dynamic adaptability and mechanical support characteristics by reversible dynamic covalent crosslinking and static covalent crosslinking, serving as an ideal scaffold for tissue engineering. Consequently, chondrocytes treated with PG/pRunx1 polyplex nanoparticles are incorporated into the hydrogels to construct tissue-engineered auricular cartilage scaffolds. After subcutaneous implantation in nude mice, the scaffolds containing chondrocytes treated with PG/pRunx1 nanoparticles showed more mature cartilaginous tissue, characterized by prominent ECM deposition and enhanced chondrogenesis. Therefore, this research provides a novel strategy for the development of tissue-engineered auricular cartilage scaffolds.
other
2026-05-10 | Enhanced Auricular Cartilage Regeneration via 3D-Printed Hydrogel With miR-92a-3p-Enriched Platelet-Rich Plasma-Derived Extracellular Vesicles.
Auricular cartilage reconstruction in microtia remains a formidable challenge in regenerative medicine. Although cartilage tissue engineering holds substantial promise, achieving reliable and efficient chondrogenesis remains a pressing challenge owing to the intrinsically quiescent phenotype of chondrocytes. We present engineered platelet-derived extracellular vesicles (PEVs) that enhance auricular chondrocyte chondrogenesis in a 3D-printed hydrogel, enabling safe and efficient ear regeneration. Initially, we demonstrated PEVs activated auricular chondrocytes, and sequencing identified miR-92a-3p as the key effector. Then we employed 3D bioprinting to fabricate a biomimetic ElaMA/GelMA double-network hydrogel auricular scaffold incorporating PEVs that were engineered to carry miRNA-92a-3p (miR@PEVs). In vivo, miR@PEV-laden scaffolds exhibited the most robust chondrogenesis compared with PEVs and control groups; after one month of subcutaneous implantation, their Young's modulus approached that of native human auricular cartilage. The scaffolds also preserved satisfactory auricular morphology and displayed excellent biocompatibility. In vitro, miR@PEVs enhanced chondrocyte proliferation and migration, chiefly through miR-92a-3p-mediated suppression of SMAD7 and subsequent activation of TGFβ/Smad signaling. Moreover, miR@PEVs promoted macrophage polarization toward the M2 phenotype, creating an immunological milieu conducive to cartilage formation. Altogether, integrating miR-92a-3p-enriched miR@PEVs into the 3D-printed ElaMA/GelMA scaffold overcomes the key hurdles of auricular reconstruction and represents a promising strategy for total ear reconstruction.
2026-01-01 | The Role of Non-Coding RNAs in Microtia: A Systematic Review of Expression Profiles and Molecular Pathways Related to Auricular Cartilage Development
Microtia is a congenital anomaly characterized by incomplete development of the external ear, ranging from mild structural abnormalities to severe auricular hypoplasia or absence of the pinna. Although several genetic and environmental factors have been associated with microtia, the underlying molecular mechanisms responsible for disrupted auricular development remain poorly understood. Increasing evidence suggests that non-coding RNAs (ncRNAs), which regulate gene expression without encoding proteins, may play a critical role in embryonic development and cartilage formation. However, the specific contribution of ncRNAs to the pathogenesis of microtia has not been comprehensively synthesized. The purpose of this systematic review is to evaluate the current evidence regarding the expression profiles of ncRNAs in individuals with microtia and to identify the molecular pathways through which these molecules may influence auricular cartilage development. Specifically, this review focuses on different classes of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), enhancer RNAs (eRNAs), and circular RNAs (circRNAs), within the microtia–atresia spectrum. By consolidating findings from available studies, this project aims to clarify how dysregulated ncRNA expression may affect processes essential for normal ear morphogenesis, such as chondrocyte proliferation, differentiation, apoptosis, extracellular matrix remodeling, and developmental signaling pathways. A systematic review methodology following the PRISMA 2020 guidelines was employed. Electronic databases, including PubMed, ScienceDirect, and Scopus, were searched to identify relevant studies published between 2011 and 2026. Studies investigating ncRNA expression in microtia tissues or biological samples were included. Two independent reviewers conducted study selection and data extraction, while methodological quality was assessed using the Newcastle–Ottawa Scale. Due to heterogeneity among the included studies, findings were synthesized narratively. The expected outcomes of this research include the identification of consistently dysregulated ncRNAs associated with microtia and the characterization of their regulatory networks and downstream targets involved in auricular development. By highlighting candidate ncRNAs and molecular pathways implicated in microtia pathogenesis, this review may provide a foundation for future functional studies and contribute to the discovery of novel biomarkers for diagnosis or prognosis. Furthermore, a deeper understanding of ncRNA-mediated mechanisms could eventually support the development of targeted therapeutic strategies and advance the field of regenerative medicine and tissue engineering for craniofacial anomalies. Overall, this project seeks to bridge existing knowledge gaps regarding the molecular basis of microtia and provide a comprehensive overview of the emerging role of non-coding RNAs in external ear development and disease.
2025-07-30 | Data Sheet 1_IL-6 signaling is required for the development and regeneration of ear cartilage in microtia.zip
Introduction Congenital microtia is a birth defect characterized by auricular underdevelopment, with unclear pathogenesis and unidentified pathogenic genes. Methods Differential expression analysis, weighted co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks and support vector machine recursive feature elimination (SVM-RFE) identified the key biomolecules in microtia. Single-cell and intercellular communication analysis were used to decipher the key intercellular signaling pathway. We extracted primary cells and conducted Immuno precipitation mass spectrometry (IP-MS), co-Immuno precipitation (Co-IP) and RNA-sequencing (RNA-seq) to confirmed the mechanism. The intercellular communication network was confirmed through the cell co-culture system. Organoid and animal models further validated the role of key biomolecules. Results We found that IL-6 may be the key biomolecule in microtia. Normal ear cartilage tissue is mainly composed of chondrocytes, but microtia auricular ear tissue contained chondrocytes and stem cells. IL-6 signaling pathway is the main intercellular communication pathways in microtia. We extracted primary chondrocytes and stem cells, and proved that IL-6 promotes the growth and migration of primary cells. The binding of IL-6 and IL-6R and Glycoprotein 130 (GP130) and the activation of their downstream were confirmed. Furthermore, IL-6 signaling pathway was proved to involve in the intercellular communication of microtia. Cartilage microspheres demonstrated the role of IL-6 in regeneration of ear cartilage. The preventive intervention of adeno-associated virus (AAV) on pregnant mice confirmed the role of IL-6 in vivo. Conclusion IL-6 signaling is the key biomolecule in the development and regeneration of auricular cartilage in microtia. IL-6 is a potential biomarker and preventive and therapeutic target for microtia patients.
2025-07-30 | IL-6 signaling is required for the development and regeneration of ear cartilage in microtia
Introduction Congenital microtia is a birth defect characterized by auricular underdevelopment, with unclear pathogenesis and unidentified pathogenic genes. Methods Differential expression analysis, weighted co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks and support vector machine recursive feature elimination (SVM-RFE) identified the key biomolecules in microtia. Single-cell and intercellular communication analysis were used to decipher the key intercellular signaling pathway. We extracted primary cells and conducted Immuno precipitation mass spectrometry (IP-MS), co-Immuno precipitation (Co-IP) and RNA-sequencing (RNA-seq) to confirmed the mechanism. The intercellular communication network was confirmed through the cell co-culture system. Organoid and animal models further validated the role of key biomolecules. Results We found that IL-6 may be the key biomolecule in microtia. Normal ear cartilage tissue is mainly composed of chondrocytes, but microtia auricular ear tissue contained chondrocytes and stem cells. IL-6 signaling pathway is the main intercellular communication pathways in microtia. We extracted primary chondrocytes and stem cells, and proved that IL-6 promotes the growth and migration of primary cells. The binding of IL-6 and IL-6R and Glycoprotein 130 (GP130) and the activation of their downstream were confirmed. Furthermore, IL-6 signaling pathway was proved to involve in the intercellular communication of microtia. Cartilage microspheres demonstrated the role of IL-6 in regeneration of ear cartilage. The preventive intervention of adeno-associated virus (AAV) on pregnant mice confirmed the role of IL-6 in vivo . Conclusion IL-6 signaling is the key biomolecule in the development and regeneration of auricular cartilage in microtia. IL-6 is a potential biomarker and preventive and therapeutic target for microtia patients.
2024-09-25 | JAG2: A Potential Biomarker for Microtia Identified by Integrated RNA Transcriptome Analysis
Introduction: Microtia, a prevalent congenital maxillofacial deformity, significantly impacts the physical and psychological health of children. Its etiology, especially in non-syndromic cases, remains a complex and partially understood domain, complicating etiological treatment. Recent studies pointed to a genetic predisposition in non-syndromic microtia, yet research on susceptible or pathogenic genes is limited. Objective: This study focused on identifying key biomarker genes in microtia cartilage to elucidate pathogenesis and assist in prenatal diagnosis. Methods: We first collated two bulk transcriptome datasets from the GEO database, followed by functional enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA) to pinpoint differentially expressed genes (DEGs) and gene modules. The subsequent intersection of DEGs with WGCNA modules, aided by support vector machine-recursive feature elimination (SVM-RFE) and protein-protein interaction (PPI) networks, predicted potential susceptibility genes for microtia. Finally, we integrated bulk RNA sequencing with single-cell data via the “scissor” R package and further validated it with Real-time PCR and immunofluorescence. Results: We identified JAG2 as a prominent biomarker for microtia, evidenced by its significant upregulation in microtia cartilage. result: we identified JAG2 as a prominent biomarker for microtia, evidenced by its significant upregulation in microtia cartilage, further validated by RT-PCR and immunofluorescence Conclusion: Our findings implicate JAG2 in microtia development and suggest its role in chondrocyte maturation and differentiation through Notch signaling pathway activation, shedding light on the potential pathogenesis of microtia.
cell therapies
2026-09-17 | Evolution and Hotspots in Autologous Ear Reconstruction: A Bibliometric Analysis of the 100 Most-cited Studies.
Autologous auricular reconstruction has evolved from cartilage-carving techniques that established modern microtia repair to an expanding regenerative and biofabrication literature. However, the field has not been mapped bibliometrically using an autologous-only lens that separates the clinical literature from emerging tissue-engineering hotspots. A Scopus search in January 2026 identified publications on autologous auricular reconstruction. Records were sorted by citation count, screened for eligibility, and the 100 most-cited studies were included. Data extracted included citations, citations per year, year, journal, country, and evidence category. Studies were classified into 4 domains: surgical technique, tissue engineering/basic science, complications/management, and outcomes/quality of life. VOSviewer was used for coauthorship and keyword co-occurrence mapping. Temporal shifts were assessed by comparing the older versus newer halves. The 100 most-cited studies (1971-2023) accrued a mean of 82.97 citations (range, 27-510) with a median of 3.46 citations per year. Most studies were clinical (71%), followed by preclinical (19%) and evidence synthesis (10%). Surgical technique predominated overall (53%), but decreased from 66% in the older half to 40% in the newer half, whereas tissue engineering increased from 16% to 28%. The most-cited article was the description by Nagata of a 2-stage, 3-dimensional costal cartilage framework (1993, Plastic and Reconstructive Surgery). Keyword clustering revealed a temporally newer regenerative cluster centered on chondrocytes, tissue engineering, and biomechanics. The citation canon of autologous auricular reconstruction is built on the late 20th-century technique classics, whereas contemporary influence is increasingly driven by regenerative medicine and biofabrication. Future high-impact work will likely be defined by durable, shape-stable engineered constructs validated in clinically relevant models.
2026-09-16 | Auricular cartilage tissue engineering: from making cartilage to regenerating a shape-stable elastic organ.
Auricular cartilage tissue engineering has long been grouped under the broader category of craniofacial cartilage reconstruction, but this classification is becoming insufficient. Unlike articular cartilage repair, which mainly aims to restore load-bearing function and relieve pain, auricular reconstruction must reproduce a complex three-dimensional structure, preserve elastic recoil, resist long-term contraction, tolerate soft-tissue coverage, and remain surgically and aesthetically acceptable over time. These demands make auricular cartilage engineering fundamentally distinct from generic cartilage engineering. Over the past decade, the field has progressed from proof-of-concept ear-shaped constructs in small-animal models to more advanced strategies, including patient-specific scaffold design, expansion of autologous auricular chondrocytes, coculture systems, decellularized auricular extracellular matrices, and 3D printing or bioprinting. Together, these advances indicate that auricular cartilage tissue engineering has moved beyond simple proof-of-concept. However, routine clinical translation remains constrained by unresolved challenges, including long-term shape maintenance, soft-tissue coverage, inflammatory remodeling, scaffold degradation, reproducible manufacturing, regulatory approval, and integration into pediatric reconstructive workflows. At the same time, they reveal a key conceptual limitation: many studies still define success as the formation of "cartilage-like" tissue, even though auricular regeneration ultimately requires a stable elastic organ rather than a histologically acceptable cartilage mass. In this perspective, we argue that the field has reached a stage where conceptual refinement is as important as technical innovation. Future progress, we propose, depends on three related shifts: moving from a generic chondrogenic paradigm to one centered on elastic cartilage biology; redefining scaffolds as instructive microenvironments rather than mere shape-retaining supports; and evaluating translational success not only by feasibility, but also by reproducibility, manufacturability, and long-term clinical robustness. Rather than offering another technique-centered review of auricular reconstruction, this Perspective advances an auricular-specific framework for defining success in elastic organ regeneration. The next major advances, in our view, will come from approaches that integrate elastic cartilage biology, instructive scaffold design, and measurable translational criteria rather than optimizing these dimensions separately.
2026-09-09 | A Ten-Year Retrospective Cohort Study on Auricular Reconstruction: Comparative Analysis of Three Surgical Techniques.
Microtia significantly impacts patients' quality of life due to physical, financial, and psychological burdens. Auricular reconstruction, the main treatment for microtia, is considered a significant challenge, given its high demand, complex nature, and need for meticulous precision. This study conducted a retrospective analysis of three widely used techniques for auricular reconstruction within our clinical practice over a 10-year period, providing substantial comparative insights and experiences into the customization of auricular reconstruction. From January 2015 to January 2025, our center performed auricular reconstruction on 1677 microtia patients. Of these, 1582 completed follow-up and joined the study. In the patient cohort, 402 received the modified two-step method, 462 had the expanded two-flap technique, and 718 underwent the single-expanded flap procedure. The cumulative operative time, total length of postoperative hospital stays, duration of therapy, and incidence of postoperative complications across all surgical stages within three distinct groups were analyzed. Additionally, patients' satisfaction with surgical outcomes was assessed. The patients were followed up for between 6 months and 10 years. The single-expanded flap technique achieved the highest satisfaction score. The modified two-step method group demonstrated the shortest cumulative operative time, and duration of therapy. The benefits, limitations, and distinct attributes of each method's application were subsequently examined and synthesized. Auricles reconstructed using the single-expanded flap technique exhibit minimal scarring, uniform color, and greater patient satisfaction. However, no single approach can be universally suitable for every patient. Thorough preoperative assessments and careful selection of indications ultimately yield positive outcomes in auricle reconstruction procedures. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
2026-09-01 | "Bio-Hammock" technique for prevention of expander inferior displacement in auricular reconstruction: A retrospective comparative cohort study of 198 patients.
Inferior displacement of tissue expanders during first-stage auricular reconstruction remains a persistent clinical challenge. We evaluated a modified dual-plane "bio-hammock" technique, in which the inferior pole of the expander (approximately 1.5-2.0 cm) is embedded within an intramuscular pocket fashioned within the sternocleidomastoid muscle (SCM) belly, because of its efficacy in preventing inferior displacement and reducing complications. A retrospective cohort study was conducted on 198 patients with unilateral microtia who underwent first-stage expander implantation between January 2022 and December 2025. The modified dual-plane cohort (n=99) was treated using the modified dual-plane technique and conventional single-plane cohort (n=99) was treated using the conventional single-plane technique. All expanders (80 ml) were over-inflated to approximately 110 ml (137.5% of nominal volume). The primary outcome was inferior displacement distance prior to the second-stage procedure and secondary outcomes included complication rates, VAS pain scores, and patient satisfaction. Inferior displacement was significantly reduced in the modified dual-plane cohort compared with the conventional single-plane cohort [median 0.30 (IQR: 0.22-0.38) cm vs. 1.40 (IQR: 1.15-1.70) cm; P<0.001], representing a 78.6% reduction. The overall complication rate was 2.0% vs. 7.1% (P=0.170), with zero expander exposure in the modified dual-plane cohort vs. 4.0% in the conventional single-plane cohort (P=0.121). Early postoperative VAS scores were marginally higher in the modified dual-plane cohort; however, they normalized by postoperative day 7. The "bio-hammock" technique provides superior mechanical stability against gravitational inferior displacement under extreme over-inflation conditions, with a favorable safety profile including zero expander exposure. This technique represents a safe and effective refinement for first-stage auricular reconstruction.
2026-07-06 | Engineering the Auricular Cartilage by Hydrogel‐ and Microgel‐Based 3D Bioprinted Constructs—An Update
ABSTRACT Auricular cartilage defects, resulting from congenital malformations such as microtia or acquired causes including trauma, infections, and tumor resection, significantly impair facial symmetry, auditory function, and psychosocial well‐being. Conventional reconstruction methods, such as autologous costal cartilage grafting and alloplastic implants, have limitations, including donor‐site morbidity, infection risk, calcification, immune rejection, and an inability to replicate the auricle's complex architecture and elastic biomechanics. To address these challenges, researchers have developed biomaterial‐based scaffolds that offer high tissue compatibility, precise shape fidelity, and minimally invasive delivery. In this regard, three‐dimensional (3D) bioprinting has emerged as a transformative technology, enabling the fabrication of patient‐specific constructs with controlled spatial deposition of biomaterials, bioactive molecules, and living cells, thereby facilitating the generation of functional auricular cartilage. This review presents the essential design criteria for bioinks tailored to auricular cartilage bioprinting, encompassing cell sourcing strategies, rheological properties and printability, bioactive factor incorporation, and mechanical performance. It then overviews recent advances in hydrogel‐ and microgel‐based bioinks for 3D and four‐dimensional (4D) bioprinting of patient‐specific auricular constructs, emphasizing natural, synthetic, and hybrid hydrogel systems. Finally, the review discusses current material and technological limitations and outlines prospective research directions to guide future studies and accelerate innovations in auricular cartilage regeneration.
small molecules
2026-06-01 | Management of Acute Postoperative Infections Following Microtia Reconstruction With Costal Cartilage Grafts.
Acute postoperative infection is a serious complication of microtia. This study analyzes infection rates and treatment outcomes to identify risk factors and improve infection control strategies. We reviewed data from June 2014 to May 2024 for 630 ears (577 patients) that underwent costal cartilage grafting and 573 ears (527 patients) that underwent ear elevation. The primary endpoint was infection onset within 1 month after surgery and clinical outcome. Secondary endpoints included remnant cartilage classification, hairline position, case type (primary versus secondary cases), medical history and comorbidities, operative time, length of hospital stay, hematoma or local wound complications, and the method of cartilage framework fixation. In addition, the timing, causative organisms, and management of infections were investigated. Infection and cartilage framework removal rates were significantly higher in the costal cartilage grafting group. Univariate and multivariate analyses revealed that hematoma, secondary cases, and local wound complications were independent risk factors for postoperative infection in the costal cartilage grafting group. Early aggressive irrigation and debridement allowed preservation of the cartilage framework, and approximately 58% of these cases maintained an auricular contour comparable to that before infection. Hematoma, secondary cases, and local wound complications were independent risk factors for acute infection after costal cartilage grafting. Surgical procedures focusing on hematoma prevention and adequate flap perfusion are important to reduce infection risk. Early surgical intervention with systemic antibiotics in the initial phase of infection may help preserve the grafted cartilage and achieve successful auricular reconstruction.
2026-02-13 | Clinical Salvage Approaches for Surgical Site Infection After Autologous Microtia Reconstruction.
Background/Objectives: Surgical site infection (SSI) after autologous rib cartilage microtia reconstruction is an uncommon but potentially devastating complication, as infection of the avascular cartilage framework can rapidly lead to partial or complete framework loss. Traditional management often favored aggressive debridement or framework removal, resulting in significant deformity. This study aimed to evaluate salvage-oriented management strategies and to propose a structured treatment algorithm for SSI following microtia reconstruction. Methods: A retrospective case series was conducted of patients who developed SSI after autologous rib cartilage microtia reconstruction between March 2021 and November 2025. SSI was defined by clinical and surveillance criteria requiring intervention beyond routine postoperative care. Nine patients were included. Management strategies were analyzed with respect to infection control, framework preservation, and wound healing outcomes. Results: SSI occurred at variable time points, ranging from early postoperative infection to delayed and late-onset presentations. Identified pathogens included Gram-positive cocci and multidrug-resistant Gram-negative organisms. Negative-pressure wound therapy (NPWT) was applied in all cases with wound dehiscence, persistent drainage, or cartilage exposure. Conservative staged debridement was performed only after clear demarcation of nonviable tissue. Overall auricular framework preservation was achieved in 100% of patients, with no cases requiring complete framework removal, although limited cartilage loss occurred in select cases. These outcomes demonstrate the clinical feasibility and effectiveness of salvage-oriented management across heterogeneous infection scenarios. Conclusions: SSI following autologous microtia reconstruction can be effectively salvaged without routine framework removal through a structured, timing-based algorithm emphasizing early culture-guided antimicrobial therapy, NPWT, and conservative staged intervention. This salvage-oriented approach provides a clinically relevant and reproducible framework for preserving auricular structure while minimizing morbidity, even in infections involving multidrug-resistant organisms.
2025-12-27 | CRABP2 Upregulation in Perichondral Stem Cells is Associated with Microtia
Abstract Microtia is a common congenital craniofacial malformation characterized by the partial or complete absence of the external ear structure. Despite its relatively high incidence, the pathogenesis of microtia remain poorly understood. In this study, we analyzed both single-cell and bulk RNA sequencing data from microtia cases and identified a population of COL1 + HES1 + mesenchymal stem cell in perichondrium with significantly higher expression of the CRABP2 gene, a gene that encodes a nuclear transporter of retinoic acid. Gene expression analysis further confirmed that the RA signaling intensity and stemness are both higher in COL1 + HES1 + perichondral stem cells from microtia patients, possibly due to elevated CRABP2 levels. Through histological verification we further confirmed the presence of this cell population with high CRABP2 expression in the perichondrium. Mechanistically, the elevated CRABP2 expression in perichondral stem cells seen in microtia patients may cause dysregulated RA signaling and disrupt the regulation of stem cell differentiation during auricular development. Histological analysis further revealed higher KLF2 expression as well as cartilage hypoplasia in microtia samples. Our study identified that the CRABP2-induced RA dysregulation in COL1 + HES1 + perichondral stem cells may contribute to microtia. These findings offer new insights into the etiology of microtia and provide potential directions for prenatal prevention and tissue engineering treatments.
2024-09-30 | Abdominal muscles infiltration analgesia for donor-site pain in autologous ear reconstruction: A randomized controlled clinical trial.
Costal cartilage donor-site pain is an adverse effect of autologous ear reconstruction. This study aimed to introduce rectus abdominis and external oblique muscle infiltration analgesia (RAM+EOM-IA) for costal cartilage donor-site pain and evaluate its efficacy and safety. The study was a randomized controlled clinical trial. Patients were randomized between intermittent RAM+EOM-IA combined with intravenous patient-controlled anesthesia (IPCA) and IPCA alone. Thirty patients were followed in the RAM+EOM-IA combined with the IPCA group and 30 patients in the IPCA alone group. The primary outcome was the numerical rating score (NRS) of pain recorded during 48 h postoperatively. Secondary outcomes included the Barthel index (BI) and rescue analgesic consumption. Sensory block areas were tested using a cold stimulus. NRS was significantly lower with RAM+EOM-IA combined with IPCA than with IPCA alone at 28 h (P < 0.01), 32 h (P < 0.01), 36 h (P < 0.01), 44 h (P < 0.001), and 48 h (P < 0.01) postoperatively. The number of patients who received rescue analgesics (P < 0.01) and consumption (P < 0.01) was significantly higher for IPCA alone. RAM+EOM-IA improved the BI at 24 h postoperatively (P < 0.001), especially for mobility (P < 0.001), using the stairs (P < 0.001) and toilet use domains (P < 0.001). At 10 and 60 min after RAM+EOM-IA, the total sensory block area in the abdomen had not extended proximally beyond the xiphoid, distally beyond the navel, and beyond midaxillary and midsternal lines on either side. RAM+EOM-IA effectively and safely prevented costal cartilage donor-site pain by blocking anterior and lateral cutaneous branches of intercostal nerves from T6 to T10 in microtia patients.
2024-06-05 | Decreased Tiam1-mediated Rac1 activation is responsible for impaired directional persistence of chondrocyte migration in microtia.
The human auricle has a complex structure, and microtia is a congenital malformation characterized by decreased size and loss of elaborate structure in the affected ear with a high incidence. Our previous studies suggest that inadequate cell migration is the primary cytological basis for the pathogenesis of microtia, however, the underlying mechanism is unclear. Here, we further demonstrate that microtia chondrocytes show a decreased directional persistence during cell migration. Directional persistence can define a leading edge associated with oriented movement, and any mistakes would affect cell function and tissue morphology. By the screening of motility-related genes and subsequent confirmations, active Rac1 (Rac1-GTP) is identified to be critical for the impaired directional persistence of microtia chondrocytes migration. Moreover, Rho guanine nucleotide exchange factors (GEFs) and Rho GTPase-activating proteins (GAPs) are detected, and overexpression of Tiam1 significantly upregulates the level of Rac1-GTP and improves directional migration in microtia chondrocytes. Consistently, decreased expression patterns of Tiam1 and active Rac1 are found in microtia mouse models, Bmp5se/J and Prkralear-3J/GrsrJ. Collectively, our results provide new insights into microtia development and therapeutic strategies of tissue engineering for microtia patients.
proteins
2026-06-10 | Modern methods of cartilaginous microtia reconstruction.
The purpose of this manuscript is to review current literature of modern cartilaginous microtia reconstruction techniques and describe evolving biotechnological advancements within this field. We additionally offer opinions on technical refinements from our institutional experience with autologous rib cartilage reconstruction performed for nearly 30 years. Autologous rib cartilage reconstruction is the gold standard for microtia treatment. There is active research in developing alternative framework materials, including allogenic and tissue-engineered cartilage. Advancements in technology such as three-dimensional bioprinting play an increasing role in the personalization and precision of auricular reconstruction. Microtia reconstructive surgery presents a challenge in balancing aesthetic goals with minimal morbidity. Cartilage offers framework strength as well as pliability for custom shaping. Tissue-engineered cartilage for microtia is promising, prompting research in this field focused on elucidating long-term durability and safety. A robust understanding of cartilaginous options for auricular reconstruction in the context of modern evidence and technology can improve both patient and surgeon satisfaction.
2026-02-06 | Analysis of Eya1 and Tbx1 mutants highlights interactions between the muscle and developing cartilage during external ear formation.
Microtia is a common feature of several human syndromes affecting the external ear (pinna), yet the cellular and molecular mechanisms remain poorly understood. Using human embryos and mouse models of branchio-oto-renal (BOR) and 22q11.2 deletion syndromes, we show that the syndromic genes Eya1 and Tbx1 are expressed in mesoderm-derived auricular muscle. In Eya1 mutant mice, auricular muscles failed to form and pinna morphogenesis was disrupted, with comparable defects observed in mesoderm-specific Tbx1 mutants. Both mutant pinnae exhibited impaired cartilage differentiation, suggesting that auricular muscle provides signals to the neural crest-derived mesenchyme to regulate cartilage differentiation. In contrast, defects in cartilage development alone or loss of muscle contraction did not affect early pinna morphogenesis. Auricular myocytes expressed Fgfs, while the surrounding mesenchyme expressed Fgfr1, Fgfr2 and ERM proteins. Disrupted Fgf signalling was observed in mutant cartilage and muscle. In ex vivo cultures, inhibition of Fgf or Bmp signalling recapitulated cartilage defects, whereas BMP4 restored Sox9 expression. These findings identify the mesoderm as essential for pinna initiation and morphogenesis, and reveal signalling mechanisms underlying microtia in BOR and 22q11.2 deletion syndromes.
2024-12-17 | Lactoferrin Stimulates Chondrogenesis and Promotes Healing of the Auricular Elastic Cartilage
Ear reconstruction surgeries, including those addressing congenital deformities like microtia and trauma-induced damages, are relatively common. Given the demand, seeking new approaches to cartilage regeneration is crucial to improving surgical outcomes, reducing recovery times, and enhancing the quality of life for patients. The natural and cost-effective protein lactoferrin (LF) draws significant attention. It is renowned for its anti-inflammatory, antimicrobial properties, and its ability to stimulate chondrogenesis of the hyaline cartilage. This study investigates the effects of LF on the viability, proliferation, and chondrogenesis of rabbit auricular chondrocytes using both in vitro and in vivo models. In vitro, LF significantly increased the metabolic activity of chondrocytes in a dose-dependent manner, with an optimal concentration of 10 μg/ml enhancing cell prolifera-tion and metabolic activity. At this concentration, it also stimulated chondrogenesis. For in vivo studies, a rabbit ear defect model was used. Macroscopic and histological analyses revealed that LF-treated groups exhibited more mature cartilage regeneration, with higher density and organi-zation of elastic fibers compared to control. These findings suggest that LF promotes auricular chondrocyte chondrogenesis and could be beneficial for tissue engineering and clinical applications in cartilage repair.
2024-03-06 | A Case of Parotid Gland Fistula After Microtia Reconstruction Successfully Treated With Botulinum Toxin Type A.
Parotid gland fistula after microtia reconstruction is relatively rare, with only 3 cases having been reported in the literature. It may be caused by the presence of an accessory parotid gland or surgical damage to parotid gland tissues. The principal treatment is dressing the wound. Here, we report the first case of parotid fistula after microtia reconstruction using a delayed retroauricular flap, which healed following wound dressing and an injection of botulinum toxin type A (CBTXA) into the parotid gland.
2023-11-22 | BMP9 is a potent inducer of chondrogenesis, volumetric expansion and collagen type II accumulation in bovine auricular cartilage chondroprogenitors
Reconstruction of the outer ear currently requires harvesting of cartilage from the posterior of the auricle or ribs leading to pain and donor site morbidity. An alternative source for auricular reconstruction is in vitro tissue engineered cartilage using stem/progenitor cells. Several candidate cell-types have been studied with tissue-specific auricular cartilage progenitor cells (AuCPC) of particular interest. Whilst chondrogenic differentiation of competent stem cells using growth factor TGFβ1 produces cartilage this tissue is frequently fibrocartilaginous and lacks the morphological features of hyaline cartilage. Recent work has shown that growth factor BMP9 is a potent chondrogenic and morphogenetic factor for articular cartilage progenitor cells, and we hypothesised that this property extends to cartilage-derived progenitors from other tissues. In this study we show monoclonal populations of AuCPCs from immature and mature bovine cartilage cultured with BMP9 produced cartilage pellets have 3-5-fold greater surface area in sections than those grown with TGFβ1. Increased volumetric growth using BMP9 was due to greater sGAG deposition in immature pellets and significantly greater collagen accumulation in both immature and mature progenitor pellets. Polarised light microscopy and immunohistochemical analyses revealed that the organisation of collagen fibrils within pellets is an important factor in the growth of pellets. Additionally, chondrocytes in BMP9 stimulated cell pellets had larger lacunae and were more evenly dispersed throughout the extracellular matrix. Interestingly, BMP9 tended to normalise the response of immature AuCPC monoclonal cell lines to differentiation cues whereas cells exhibited more variation under TGFβ1. In conclusion, BMP9 appears to be a potent inducer of chondrogenesis and volumetric growth for AuCPCs a property that can be exploited for tissue engineering strategies for reconstructive surgery though with the caveat of negligible elastin production following 21-day treatment with either growth factor.
gene therapies
2026-09-26 | Relationship Between External Ear Severity and Temporal Bone Malformation in Microtia: A Computed Tomography Study.
Background/Objectives: Microtia is frequently associated with temporal bone malformations, but the extent to which external ear phenotype reflects underlying CT-defined anatomy remains uncertain. This study aimed to compare the relationships of Marx severity grading and Nagata morphological classification with temporal bone anatomy in patients with microtia. Methods: This retrospective study included 26 patients with 27 affected ears who had both preoperative external ear photographs and temporal bone computed tomography (CT) examinations. Each affected ear was classified according to the Marx and Nagata systems, and temporal bone anatomy was assessed using the modified Jahrsdoerfer CT scoring system. Associations were evaluated using Spearman rank correlation and permutation-based Jonckheere-Terpstra analysis, with an additional patient-level sensitivity analysis. Results: Considerable variation in Jahrsdoerfer scores was observed within external ear phenotypic categories, with substantial overlap between Marx Grades II and III and lower scores concentrated in Grade IV. The inverse association between Marx grade and Jahrsdoerfer score did not reach conventional statistical significance (ρ = -0.380, p = 0.051), whereas the Jonckheere-Terpstra test identified an overall decreasing trend (permutation p = 0.025). This trend no longer reached statistical significance in the patient-level sensitivity analysis. Nagata classification did not significantly discriminate CT-based radiological severity. Conclusions: Greater external auricular severity may be associated with less favorable temporal bone anatomy, but the relationship was not uniform across successive Marx grades. Marx and Nagata classifications provide complementary phenotypic information, but neither consistently reflected the extent of underlying temporal bone malformation. These preliminary findings emphasize phenotype-CT variability and support individualized CT-based anatomical assessment when imaging is clinically indicated.
2026-04-09 | Genetic variation near ROBO1 is associated with craniofacial microsomia and related phenotypes in the Finnish population.
Craniofacial microsomia (CFM) encompasses a phenotypic continuum of congenital anomalies ranging from isolated microtia to more complex manifestations within the oculo-auriculo-vertebral spectrum, including Goldenhar syndrome, reflecting abnormal development of first and second pharyngeal arch-derived structures. While several genetic susceptibility loci have been reported, population-based evidence in individuals of European ancestry remains limited. Using nationwide data from FinnGen in the Finnish founder population, we identified a genome-wide significant association at a conserved intergenic locus near ROBO1, extending previous findings to a European ancestry cohort. The lead variant, rs62256696, lies within a regulatory region active in human embryonic craniofacial tissues during early development and shows concordant association with previously reported ROBO1 signals from non-European populations. Genetic correlation analyses demonstrated strong shared genetic architecture between CFM and auditory developmental phenotypes, consistent with the defined phenotypic continuum. Together, these findings extend previous observations to a new population context and support a role for regulatory variation at the ROBO1 locus in early craniofacial morphogenesis and auditory system development underlying craniofacial and auditory malformations.
2025-12-31 | The Microtia in Treacher Collins Syndrome
Introduction: Treacher Collins Syndrome (TCS) is a condition affecting the development of facial structures. TCS presents with variable clinical manifestations and can impact the quality of life of those affected. Early identification and diagnosis are crucial management planning and intervention. Objective: To understand the embryology, genetic abnormalities, and manifestations of TCS which would facilitate the diagnosis. Methods: A narrative review of the literature published between 2010 and 2024. The literature search was conducted using the keywords "Treacher Collins Syndrome" and related terms (embryology, epidemiology, diagnosis) across academic databases such as PubMed, Google Scholar, and ScienceDirect. Result: From the 116 articles identified, a review was conducted on 23 publications deemed relevant and appropriate to the topic. Treacher Collins Syndrome (TCS), also known as Mandibulofacial Dysostosis, is a genetic disorder affecting facial structures, characterized by variable clinical manifestations. TCS has impact on the quality of life of those affected. It is inherited in an autosomal dominant manner and involves mutations in the TCOF1, POLR1D, POLR1C or POLR1B genes, which disrupts the development of the pharyngeal arches during embryogenesis. Microtia and conductive hearing loss are otology manifestations of TCS. TCS is diagnosed based on clinical manifestations, along with genetic confirmation. Conclusion: Identification and diagnosis of Treacher Collins Syndrome (TCS) are crucial for planning management and interventions that can improve the patient's quality of life.
2025-01-28 | Epidemiological Characteristics and Maternal Risk Factors of Microtia and Aural Atresia in Kazakhstan.
Introduction Microtia and aural atresia present congenital ear anomalies that affect external ear and are associated with conductive hearing loss. Both anomalies result from exposure to various prenatal risk factors, most common during the first trimester of pregnancy. Objective This study was aimed at epidemiological analysis of microtia/atresia and associated risk factors in the Kazakhstani population. Methods A retrospective study in two stages. First, a cross-sectional analysis of microtia/ atresia frequencies from 2015 to 2019 on the basis of official statistics obtained from the Republican Centre for E-Health. Then, a case-control study was carried out to elucidate maternal risk factors associated with occurrence of microtia/atresia. We recruited patients presented in Almaty, Kazakhstan, between September 2021 and February 2022. Results There was a substantial regional variation in the rates of both aural atresia and microtia/anotia. Mothers of children with microtia disclosed toxoplasmosis, other agents (including HIV, syphilis, varicella), rubella, cytomegalovirus, herpes simplex (TORCH) infections during pregnancy more often than those of healthy children (45.8 versus 7.3%; p < 0.001). Exposure to different chemicals during pregnancy was mentioned more frequently by mothers of children with microtia when compared with the healthy controls (18.1 versus 8.1%; p = 0.035). Self-reporting of alcohol consumption and intake of antibiotics was also significantly higher in mothers of children with microtia (31.9 and 36.1% respectively). Conclusion Elucidation of microtia/atresia epidemiology is important due to their imposed social and economic burden, associated with treatment and rehabilitation costs.
2025-01-02 | Double network hydrogels encapsulating genetically modified dedifferentiated chondrocytes for auricular cartilage regeneration.
Microtia profoundly affects patients' appearance and psychological well-being. Tissue engineering ear cartilage scaffolds have emerged as the most promising solution for ear reconstruction. However, constructing tissue engineering ear cartilage scaffolds requires multiple passaging of chondrocytes, resulting in their dedifferentiation and loss of their special phenotypes and functions. To tackle these issues, here we employ guanidinobenzoic acid (GBA) modified generation 5 polyamidoamine (PAMAM) dendrimers (PG) as a Runx1 plasmid carrier to construct PG/pRunx1 polyplex nanoparticles. The PG/pRunx1 polyplexes are transfected into human auricular chondrocytes, significantly mitigating chondrocyte dedifferentiation and enhancing cartilage regeneration during the in vitro culture. Furthermore, we develop highly porous double-network hydrogels based on methacrylate-functionalized and oxidized chondroitin sulfate and carbohydrazide-modified gelatin and the hydrogels possessed both dynamic adaptability and mechanical support characteristics by reversible dynamic covalent crosslinking and static covalent crosslinking, serving as an ideal scaffold for tissue engineering. Consequently, chondrocytes treated with PG/pRunx1 polyplex nanoparticles are incorporated into the hydrogels to construct tissue-engineered auricular cartilage scaffolds. After subcutaneous implantation in nude mice, the scaffolds containing chondrocytes treated with PG/pRunx1 nanoparticles showed more mature cartilaginous tissue, characterized by prominent ECM deposition and enhanced chondrogenesis. Therefore, this research provides a novel strategy for the development of tissue-engineered auricular cartilage scaffolds.
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2026-05-10 | Enhanced Auricular Cartilage Regeneration via 3D-Printed Hydrogel With miR-92a-3p-Enriched Platelet-Rich Plasma-Derived Extracellular Vesicles.
Auricular cartilage reconstruction in microtia remains a formidable challenge in regenerative medicine. Although cartilage tissue engineering holds substantial promise, achieving reliable and efficient chondrogenesis remains a pressing challenge owing to the intrinsically quiescent phenotype of chondrocytes. We present engineered platelet-derived extracellular vesicles (PEVs) that enhance auricular chondrocyte chondrogenesis in a 3D-printed hydrogel, enabling safe and efficient ear regeneration. Initially, we demonstrated PEVs activated auricular chondrocytes, and sequencing identified miR-92a-3p as the key effector. Then we employed 3D bioprinting to fabricate a biomimetic ElaMA/GelMA double-network hydrogel auricular scaffold incorporating PEVs that were engineered to carry miRNA-92a-3p (miR@PEVs). In vivo, miR@PEV-laden scaffolds exhibited the most robust chondrogenesis compared with PEVs and control groups; after one month of subcutaneous implantation, their Young's modulus approached that of native human auricular cartilage. The scaffolds also preserved satisfactory auricular morphology and displayed excellent biocompatibility. In vitro, miR@PEVs enhanced chondrocyte proliferation and migration, chiefly through miR-92a-3p-mediated suppression of SMAD7 and subsequent activation of TGFβ/Smad signaling. Moreover, miR@PEVs promoted macrophage polarization toward the M2 phenotype, creating an immunological milieu conducive to cartilage formation. Altogether, integrating miR-92a-3p-enriched miR@PEVs into the 3D-printed ElaMA/GelMA scaffold overcomes the key hurdles of auricular reconstruction and represents a promising strategy for total ear reconstruction.
2026-01-01 | The Role of Non-Coding RNAs in Microtia: A Systematic Review of Expression Profiles and Molecular Pathways Related to Auricular Cartilage Development
Microtia is a congenital anomaly characterized by incomplete development of the external ear, ranging from mild structural abnormalities to severe auricular hypoplasia or absence of the pinna. Although several genetic and environmental factors have been associated with microtia, the underlying molecular mechanisms responsible for disrupted auricular development remain poorly understood. Increasing evidence suggests that non-coding RNAs (ncRNAs), which regulate gene expression without encoding proteins, may play a critical role in embryonic development and cartilage formation. However, the specific contribution of ncRNAs to the pathogenesis of microtia has not been comprehensively synthesized. The purpose of this systematic review is to evaluate the current evidence regarding the expression profiles of ncRNAs in individuals with microtia and to identify the molecular pathways through which these molecules may influence auricular cartilage development. Specifically, this review focuses on different classes of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), enhancer RNAs (eRNAs), and circular RNAs (circRNAs), within the microtia–atresia spectrum. By consolidating findings from available studies, this project aims to clarify how dysregulated ncRNA expression may affect processes essential for normal ear morphogenesis, such as chondrocyte proliferation, differentiation, apoptosis, extracellular matrix remodeling, and developmental signaling pathways. A systematic review methodology following the PRISMA 2020 guidelines was employed. Electronic databases, including PubMed, ScienceDirect, and Scopus, were searched to identify relevant studies published between 2011 and 2026. Studies investigating ncRNA expression in microtia tissues or biological samples were included. Two independent reviewers conducted study selection and data extraction, while methodological quality was assessed using the Newcastle–Ottawa Scale. Due to heterogeneity among the included studies, findings were synthesized narratively. The expected outcomes of this research include the identification of consistently dysregulated ncRNAs associated with microtia and the characterization of their regulatory networks and downstream targets involved in auricular development. By highlighting candidate ncRNAs and molecular pathways implicated in microtia pathogenesis, this review may provide a foundation for future functional studies and contribute to the discovery of novel biomarkers for diagnosis or prognosis. Furthermore, a deeper understanding of ncRNA-mediated mechanisms could eventually support the development of targeted therapeutic strategies and advance the field of regenerative medicine and tissue engineering for craniofacial anomalies. Overall, this project seeks to bridge existing knowledge gaps regarding the molecular basis of microtia and provide a comprehensive overview of the emerging role of non-coding RNAs in external ear development and disease.
2025-07-30 | Data Sheet 1_IL-6 signaling is required for the development and regeneration of ear cartilage in microtia.zip
Introduction Congenital microtia is a birth defect characterized by auricular underdevelopment, with unclear pathogenesis and unidentified pathogenic genes. Methods Differential expression analysis, weighted co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks and support vector machine recursive feature elimination (SVM-RFE) identified the key biomolecules in microtia. Single-cell and intercellular communication analysis were used to decipher the key intercellular signaling pathway. We extracted primary cells and conducted Immuno precipitation mass spectrometry (IP-MS), co-Immuno precipitation (Co-IP) and RNA-sequencing (RNA-seq) to confirmed the mechanism. The intercellular communication network was confirmed through the cell co-culture system. Organoid and animal models further validated the role of key biomolecules. Results We found that IL-6 may be the key biomolecule in microtia. Normal ear cartilage tissue is mainly composed of chondrocytes, but microtia auricular ear tissue contained chondrocytes and stem cells. IL-6 signaling pathway is the main intercellular communication pathways in microtia. We extracted primary chondrocytes and stem cells, and proved that IL-6 promotes the growth and migration of primary cells. The binding of IL-6 and IL-6R and Glycoprotein 130 (GP130) and the activation of their downstream were confirmed. Furthermore, IL-6 signaling pathway was proved to involve in the intercellular communication of microtia. Cartilage microspheres demonstrated the role of IL-6 in regeneration of ear cartilage. The preventive intervention of adeno-associated virus (AAV) on pregnant mice confirmed the role of IL-6 in vivo. Conclusion IL-6 signaling is the key biomolecule in the development and regeneration of auricular cartilage in microtia. IL-6 is a potential biomarker and preventive and therapeutic target for microtia patients.
2025-07-30 | IL-6 signaling is required for the development and regeneration of ear cartilage in microtia
Introduction Congenital microtia is a birth defect characterized by auricular underdevelopment, with unclear pathogenesis and unidentified pathogenic genes. Methods Differential expression analysis, weighted co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks and support vector machine recursive feature elimination (SVM-RFE) identified the key biomolecules in microtia. Single-cell and intercellular communication analysis were used to decipher the key intercellular signaling pathway. We extracted primary cells and conducted Immuno precipitation mass spectrometry (IP-MS), co-Immuno precipitation (Co-IP) and RNA-sequencing (RNA-seq) to confirmed the mechanism. The intercellular communication network was confirmed through the cell co-culture system. Organoid and animal models further validated the role of key biomolecules. Results We found that IL-6 may be the key biomolecule in microtia. Normal ear cartilage tissue is mainly composed of chondrocytes, but microtia auricular ear tissue contained chondrocytes and stem cells. IL-6 signaling pathway is the main intercellular communication pathways in microtia. We extracted primary chondrocytes and stem cells, and proved that IL-6 promotes the growth and migration of primary cells. The binding of IL-6 and IL-6R and Glycoprotein 130 (GP130) and the activation of their downstream were confirmed. Furthermore, IL-6 signaling pathway was proved to involve in the intercellular communication of microtia. Cartilage microspheres demonstrated the role of IL-6 in regeneration of ear cartilage. The preventive intervention of adeno-associated virus (AAV) on pregnant mice confirmed the role of IL-6 in vivo . Conclusion IL-6 signaling is the key biomolecule in the development and regeneration of auricular cartilage in microtia. IL-6 is a potential biomarker and preventive and therapeutic target for microtia patients.
2024-09-25 | JAG2: A Potential Biomarker for Microtia Identified by Integrated RNA Transcriptome Analysis
Introduction: Microtia, a prevalent congenital maxillofacial deformity, significantly impacts the physical and psychological health of children. Its etiology, especially in non-syndromic cases, remains a complex and partially understood domain, complicating etiological treatment. Recent studies pointed to a genetic predisposition in non-syndromic microtia, yet research on susceptible or pathogenic genes is limited. Objective: This study focused on identifying key biomarker genes in microtia cartilage to elucidate pathogenesis and assist in prenatal diagnosis. Methods: We first collated two bulk transcriptome datasets from the GEO database, followed by functional enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA) to pinpoint differentially expressed genes (DEGs) and gene modules. The subsequent intersection of DEGs with WGCNA modules, aided by support vector machine-recursive feature elimination (SVM-RFE) and protein-protein interaction (PPI) networks, predicted potential susceptibility genes for microtia. Finally, we integrated bulk RNA sequencing with single-cell data via the “scissor” R package and further validated it with Real-time PCR and immunofluorescence. Results: We identified JAG2 as a prominent biomarker for microtia, evidenced by its significant upregulation in microtia cartilage. result: we identified JAG2 as a prominent biomarker for microtia, evidenced by its significant upregulation in microtia cartilage, further validated by RT-PCR and immunofluorescence Conclusion: Our findings implicate JAG2 in microtia development and suggest its role in chondrocyte maturation and differentiation through Notch signaling pathway activation, shedding light on the potential pathogenesis of microtia.
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Drug Discovery Landscape
2 orphan drug designations for Microtia.
2 orphan drug designations for Microtia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Autologous auricular cartilage construct for subcutaneous implantation | cell therapies | FDA | — | PrintBio, Inc. |
expanded human autologous chondrocytes in a biopolymer (sodium alginate, gellan gum) matrix | cell therapies | FDA | Auregen BioTherapeutics SA |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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