Publications

Associate Professor of Otolaryngology - Head & Neck Surgery (OHNS)

Publications

  • Gold nanocluster adjuvant enables the eradication of persister cells by antibiotics and abolishes the emergence of resistance. Nanoscale Cao, Z., Chen, X., Chen, J., Xia, A., Bacacao, B., Tran, J., Sharma, D., Bekale, L. A., Santa Maria, P. L. 2022

    Abstract

    Persister cells are responsible for relapses of infections common in cystic fibrosis and chronic suppurative otitis media (CSOM). Yet, there are no Food and Drug Administration (FDA) approved antibiotics to eradicate persister cells. Frustratingly, the global preclinical bacterial pipeline does not contain antibacterial agents targeting persister cells. Therefore, we report a nontraditional antimicrobial chemotherapy strategy based on gold nanoclusters adjuvant to eradicate persister cells by existing antibiotics belonging to that different class. Compared to killing with antibiotics alone, combining antibiotics and AuNC@CPP sterilizes persister cells and biofilms. Enhanced killing of up to 4 orders of magnitude in a validated mouse model of CSOM with Pseudomonas aeruginosa infection was observed when combining antibiotics and AuNC@CPP, informing a potential approach to improve the treatment of CSOM. We established that the mechanism of action of AuNC@CPP is due to disruption of the proton gradient and membrane hyperpolarization. The method presented here could compensate for the lack of new antibiotics to combat persister cells. This method could also benefit the current effort to slow resistance development because AuNC@CPP abolished the emergence of drug-resistant strains induced by antibiotics.

    View details for DOI 10.1039/d2nr01003h

    View details for PubMedID 35796201

  • Minimally invasive trans-tympanic eustachian tube occlusion animal model. International journal of pediatric otorhinolaryngology Kouhi, A., Xia, A., Khomtchouk, K., Santa Maria, P. L. 2022; 156: 111070

    Abstract

    OBJECTIVE: Eustachian tube dysfunction is believed to be involved in the pathogenesis of many middle ear diseases including chronic suppurative otitis media. We aimed to describe a simple and reliable animal model of Eustachian Tube obstruction to further research into middle ear disorders.STUDY DESIGN: Prospective cohort study in animals.SETTING: University laboratory.SUBJECTS AND METHODS: 30 mice C57Bl/6J (n=15) and CBA/CaJ (n=15) aged 6-8 weeks received transtympanic Eustachian tube occlusion on left ear trough an acute tympanic membrane perforation using thermoplastic latex used in dental procedures (gutta percha). Control mice (n=6) received tympanic membrane perforation only. At two and four weeks, the mice were observed for signs of Eustachian tube dysfunction and compared to control ears. ET dysfunction was defined as presence of effusion in the middle ear.RESULTS: 100% (n=30) of the treated ears had otoscopic signs of Eustachian tube dysfunction at two weeks and the endpoint time of four weeks, compared to 0% in control mice (0/6). Temporary head tilt lasting up to 2 days were observed in 3 mice (10%). No other potential adverse events were recorded. No bacterial growth was determined in the middle ear fluid.CONCLUSION: We describe a technically easy and reliable method for Eustachian tube occlusion in mice with an excellent success rate and minimal morbidity.

    View details for DOI 10.1016/j.ijporl.2022.111070

    View details for PubMedID 35228098

  • New Medical Device and Therapeutic Approvals in Otolaryngology: State of the Art Review 2020. OTO open Brenner, M. J., Shenson, J. A., Rose, A. S., Valdez, T. A., Takashima, M., Ahmed, O. G., Weissbrod, P. A., Hong, R. S., Djalilian, H., Wolf, J. S., Morrison, R. J., Santa Maria, P. L., Erbele, I. D. 2021; 5 (4): 2473974X211057035

    Abstract

    Objectives: To evaluate new drugs and devices relevant to otolaryngology-head and neck surgery that were approved by the US Food and Drug Administration (FDA) in 2020.Data Sources: Publicly available device and therapeutic approvals from ENT (ear, nose, and throat), anesthesia, neurology (neurosurgery), and plastic and general surgery FDA committees.Review Methods: Members of the American Academy of Otolaryngology-Head and Neck Surgery's Medical Devices and Drugs Committee reviewed new therapeutics and medical devices from a query of the FDA's device and therapeutic approvals. Two independent reviewers assessed the drug's or device's relevance to otolaryngology, classified to subspecialty field, with a critical review of available scientific literature.Conclusions: The Medical Devices and Drugs Committee reviewed 53 new therapeutics and 1094 devices (89 ENT, 140 anesthesia, 511 plastic and general surgery, and 354 neurology) approved in 2020. Ten drugs and 17 devices were considered relevant to the otolaryngology community. Rhinology saw significant improvements around image guidance systems; indications for cochlear implantation expanded; several new monoclonal therapeutics were added to head and neck oncology's armamentarium; and several new approvals appeared for facial plastics surgery, pediatric otolaryngology, and comprehensive otolaryngology.Implications for Practice: New technologies and pharmaceuticals offer the promise of improving how we care for otolaryngology patients. However, judicious introduction of innovations into practice requires a nuanced understanding of safety, advantages, and limitations. Working knowledge of new drugs and medical devices approved for the market helps clinicians tailor patient care accordingly.

    View details for DOI 10.1177/2473974X211057035

    View details for PubMedID 34790883

  • Topical Therapy Failure in Chronic Suppurative Otitis Media is Due to Persister Cells in Biofilms. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Santa Maria, P. L., Kaufman, A. C., Bacacao, B., Thai, A., Chen, X., Xia, A., Cao, Z., Fouad, A., Bekale, L. A. 2021

    Abstract

    OBJECTIVE: Chronic suppurative otitis media (CSOM) is characterized by a chronically draining middle ear. CSOM is typically treated with multiple courses of antibiotics or antiseptics which are successful in achieving quiescence; however, the disease is prone to relapse. Understanding why these treatment failures occur is essential.STUDY DESIGN: The minimum inhibitory concentration (MIC), minimal biofilm eradication concentration, and the inhibitory zone were determined for ototopicals and ofloxacin for the laboratory strains and CSOM-derived isolates. The percentage of persister cells and bacterial biofilm formation were measured. Disease eradication was tested in a validated in-vivo model of CSOM after treatment with ofloxacin.SETTING: Microbiology Laboratory.METHODS: Basic science experiments were performed to measure the effectiveness of a number of compounds against CSOM bacteria in a number of distinct settings.RESULTS: The minimal biofilm eradication concentration is higher than is physiologically achievable with commercial preparations, except for povo-iodine. Clincial isolates of CSOM have equivalent biofilm-forming ability but increased proportions of persister cells. Ofloxacin can convert to inactive disease temporarily but fails to eradicate disease in an in-vivo model.CONCLUSIONS: Higher percentages of persister cells in clinical CSOM isolates are associated with resistance to ototopicals. Current ototopicals, except povo-iodine, have limited clinical effectiveness; however, it is unknown what the maximum achievable concentration is and there are ototoxicity concerns. Fluoroquinolones, while successful in producing inactive disease in the short term, have the potential to encourage antimicrobial resistance and disease recalcitrance and do not achieve a permanent remission. Given these limitations, clinicians should consider surgery earlier or use of clinically safe concentrations of povo-iodine earlier into the treatment algorithm.

    View details for DOI 10.1097/MAO.0000000000003222

    View details for PubMedID 34149028

  • Middle Cranial Fossa Approach to Repair Tegmen Dehiscence Using Self-setting Calcium Phosphate Cement: A Retrospective Case Review. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Bulsara, V. M., Kim, G. S., Fouad, A. M., Bulsara, M. K., Santa Maria, P. L. 2021

    Abstract

    OBJECTIVES: To review the outcomes of repairing tegmen dehiscence using the middle cranial fossa approach with a self-setting bone cement.STUDY DESIGN: Retrospective case series.SETTING: Two academic tertiary hospitals.PATIENTS: All patients presenting for surgical repair of tegmen dehiscence and with postoperative follow-up for at least 6 months between October 2015 and July 2019.INTERVENTION: Surgical repair using a middle cranial fossa approach using a layered reconstruction with temporalis fascia and self-setting calcium phosphate bone cement.MAIN OUTCOME MEASURES: Perioperative complications, recurrence of presenting symptoms/disease, hearing, and facial nerve grade.RESULTS: The cohort consisted of 22 patients with 23 tegmen dehiscence repairs (1 sequential bilateral repair). There were 16 males and 6 females with an average age at operation of 52.6 years. Repairs were left sided in 9, right sided in 12 patients, and bilateral in 1 patient. No patients had recurrence of presenting symptoms or disease at most recent follow-up. Preoperative hearing was maintained in all patients. Two patients (9% of repairs) experienced delayed partial temporary facial nerve weakness House-Brackman grade 2 and 4 which had recovered by 8 weeks postoperative.CONCLUSION: We demonstrate a technique for repairing tegmen dehiscence of the middle cranial fossa floor that has excellent postoperative outcomes. We highlight potential technical challenges in this approach as well as the need for counseling for potential partial transient facial nerve dysfunction.

    View details for DOI 10.1097/MAO.0000000000003110

    View details for PubMedID 33710151

  • Antimicrobial Gold Nanoclusters Eradicate Escherichia coli Biofilms and Are Nontoxic by Oral Administration. ACS applied bio materials Cao, Z., Chen, J., Tran, J., Chen, X., Bacacao, B., Bekale, L. A., Santa Maria, P. L. 2020; 3 (8): 5275-5286

    Abstract

    Escherichia coli biofilms are a major causative agent of many intestinal infections, and there is ongoing research aimed at E. coli biofilm eradication. Gold nanoclusters (AuNCs) conjugated with various surface ligands have been extensively investigated for antimicrobial properties and provide a potential solution. There is little known about their in vivo safety because current standards of nanosafety research involve incubation of AuNCs with cells in vitro to confirm biocompatibility. In addition to systemic administration, nanosafety research on AuNC-based antimicrobials designed to treat gastrointestinal infections must also consider the potential for inducing gastrointestinal disorders. We report the design and application of two AuNCs coated with either hydroxyl (AuNC@PEG-OH)- or amine (AuNC@PEG-NH2)-functionalized poly(ethylene glycol), which enables the eradication of E. coli biofilms. Gastrointestinal safety of AuNC@PEG-OH and AuNC@PEG-NH2 was evaluated in healthy mice up to 35 days after administration by oral gavage at a dose of 10 mg/kg (or 1 mg/mL) daily for 14 days. No changes were detected in the histopathology of major organs, serum chemistry, hematology, and feces. Thus, oral administration of AuNCs is unlikely to be of concern for systemic toxicity or in the induction of gastrointestinal illnesses. Further studies on increasing time exposure and doses are necessary to determine whether toxicity occurs at higher doses or whether there is no adverse effect limit.

    View details for DOI 10.1021/acsabm.0c00641

    View details for PubMedID 35021702

  • Long-Term Hearing Outcomes Following Stereotactic Radiosurgery in Vestibular Schwannoma Patients-A Retrospective Cohort Study Santa Maria, P. L., Shi, Y., Gurgel, R. K., Corrales, C., Soltys, S. G., Santa Maria, C., Murray, K., Chang, S. D., Blevins, N. H., Gibbs, I. C., Jackler, R. K. OXFORD UNIV PRESS INC. 2019: 550–59
  • Single Administration of a Sustained-Release Formulation of KB-R7785 Inhibits Tympanic Membrane Regeneration in an Animal Model JOURNAL OF INTERNATIONAL ADVANCED OTOLOGY Maria, P. L., Maria, C. S., Kim, S., Yang, Y. P. 2016; 12 (3): 237-240

    Abstract

    A pressure equalization tube placed within the tympanic membrane is the only clinically available method for inhibiting tympanic membrane regeneration. Problems associated with this include associated otorrhea, biofilm formation, medial migration of the tube, tube retention, induction of granulation tissue, and a small but significant rate of cholesteatoma. We aimed to demonstrate that a single administration of a sustained-release polymer formulation of KB-R7785 maintains tympanic membrane perforation for at least 6 months.Sustained-release KB-R7785 was delivered within a novel polymer hydrogel to 20 mice with bilateral acute tympanic membrane perforations (a total of 40 perforations). The perforations were monitored at 3-month intervals until 9 months.At 3 months, 90% of perforations were open (n=36/40). At 6 months, 75% of perforations were open (total n=30/40). At 9 months, 22.5% of perforations were open (total n=6/40). The majority of tympanic membrane perforations (75%) were open (not healed) beyond 6 months and close (fully healed) prior to 9 months (77.5%). Once healed, tympanic membranes resembled their normal histological appearance.This study demonstrates that a single administration of a sustained-release polymer formulation of KB-R7785 inhibits tympanic membrane regeneration for 6-9 months.

    View details for DOI 10.5152/iao.2016.3124

    View details for PubMedID 28031154

  • Heparin Binding Epidermal Growth Factor-Like Growth Factor Heals Chronic Tympanic Membrane Perforations With Advantage Over Fibroblast Growth Factor 2 and Epidermal Growth Factor in an Animal Model OTOLOGY & NEUROTOLOGY Maria, P. L., Weierich, K., Kim, S., Yang, Y. P. 2015; 36 (7): 1279-1283

    Abstract

    That heparin binding epidermal growth factor-like growth factor (HB-EGF) heals chronic tympanic membrane (TM) perforations at higher rates than fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) in an animal model.A nonsurgical treatment for chronic TM perforation would benefit those unable to access surgery or those unable to have surgery, as well as reducing the cost of tympanoplasty. Growth factor (GF) treatments have been reported in the literature with variable success with the lack of a suitable animal providing a major obstacle.The GFs were tested in a validated mouse model of chronic TM perforation. A bioabsorbable hydrogel polymer was used to deliver the GF at a steady concentration as it dissolved over 4 weeks. A control (polymer only, n = 18) was compared to polymer loaded with HB-EGF (5 μg/ml, n = 18), FGF2 (100 μg/ml, n = 19), and EGF (250 μg/ml, n = 19). Perforations were inspected at 4 weeks.The healing rates, as defined as 100% perforation closure, were control (5/18, 27.8%), HB-EGF (15/18, 83.3%), FGF2 (6/19, 31.6%), and EGF (3/19, 15.8%). There were no differences between FGF2 (p = 0.80) and EGF (p = 0.31) with control healing rates. HB-EGF (p = 0.000001) showed a significant difference for healing. The HB-EGF healed TMs showed layers similar to a normal TM, whereas the other groups showed a lack of epithelial migration.This study confirms the advantage of HB-EGF over two other commonly used growth factors and is a promising nonsurgical treatment of chronic TM perforations.

    View details for DOI 10.1097/MAO.0000000000000795

    View details for Web of Science ID 000358409500021

  • Heparin Binding Epidermal Growth Factor-Like Growth Factor Heals Chronic Tympanic Membrane Perforations With Advantage Over Fibroblast Growth Factor 2 and Epidermal Growth Factor in an Animal Model. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Santa Maria, P. L., Weierich, K., Kim, S., Yang, Y. P. 2015; 36 (7): 1279-83

    Abstract

    That heparin binding epidermal growth factor-like growth factor (HB-EGF) heals chronic tympanic membrane (TM) perforations at higher rates than fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) in an animal model.A nonsurgical treatment for chronic TM perforation would benefit those unable to access surgery or those unable to have surgery, as well as reducing the cost of tympanoplasty. Growth factor (GF) treatments have been reported in the literature with variable success with the lack of a suitable animal providing a major obstacle.The GFs were tested in a validated mouse model of chronic TM perforation. A bioabsorbable hydrogel polymer was used to deliver the GF at a steady concentration as it dissolved over 4 weeks. A control (polymer only, n = 18) was compared to polymer loaded with HB-EGF (5 μg/ml, n = 18), FGF2 (100 μg/ml, n = 19), and EGF (250 μg/ml, n = 19). Perforations were inspected at 4 weeks.The healing rates, as defined as 100% perforation closure, were control (5/18, 27.8%), HB-EGF (15/18, 83.3%), FGF2 (6/19, 31.6%), and EGF (3/19, 15.8%). There were no differences between FGF2 (p = 0.80) and EGF (p = 0.31) with control healing rates. HB-EGF (p = 0.000001) showed a significant difference for healing. The HB-EGF healed TMs showed layers similar to a normal TM, whereas the other groups showed a lack of epithelial migration.This study confirms the advantage of HB-EGF over two other commonly used growth factors and is a promising nonsurgical treatment of chronic TM perforations.

    View details for DOI 10.1097/MAO.0000000000000795

    View details for PubMedID 26075672