Successful nerve repair using bioadhesive hydrogels demands minimizing tissue–material interfacial mechanical mismatch to reduce immune responses and scar tissue formation. Furthermore, it is crucial to maintain the bioelectrical stimulation-mediated cell-signaling mechanism to overcome communication barriers within injured nerve tissues. Therefore, engineering bioadhesives for neural tissue regeneration necessitates the integration of electroconductive properties with tissue-like biomechanics. In this study, we propose a stretchable bioadhesive based on a custom-designed chemically modified elastin-like polypeptides (ELPs) and a choline-based bioionic liquid (Bio-IL), providing an electroconductive microenvironment to reconnect damaged nerve tissue. The stretchability akin to native neural tissue was achieved by incorporating hydrophobic ELP pockets, and a robust tissue adhesion was obtained due to multi-mode tissue–material interactions through covalent and noncovalent bonding at the tissue interface. Adhesion tests revealed adhesive strength ~10 times higher than commercially available tissue adhesive, Evicel®. Furthermore, the engineered hydrogel supported in vitro viability and proliferation of human glial cells. We also evaluated the biodegradability and biocompatibility of the engineered bioadhesive in vivo using a rat subcutaneous implantation model, which demonstrated facile tissue infiltration and minimal immune response. The outlined functionalities empower the engineered elastic and electroconductive adhesive hydrogel to effectively enable sutureless surgical sealing of neural injuries and promote tissue regeneration.
{"title":"A stretchable, electroconductive tissue adhesive for the treatment of neural injury","authors":"Jharana Dhal, Mahsa Ghovvati, Avijit Baidya, Ronak Afshari, Curtis L. Cetrulo Jr, Reza Abdi, Nasim Annabi","doi":"10.1002/btm2.10667","DOIUrl":"10.1002/btm2.10667","url":null,"abstract":"<p>Successful nerve repair using bioadhesive hydrogels demands minimizing tissue–material interfacial mechanical mismatch to reduce immune responses and scar tissue formation. Furthermore, it is crucial to maintain the bioelectrical stimulation-mediated cell-signaling mechanism to overcome communication barriers within injured nerve tissues. Therefore, engineering bioadhesives for neural tissue regeneration necessitates the integration of electroconductive properties with tissue-like biomechanics. In this study, we propose a stretchable bioadhesive based on a custom-designed chemically modified elastin-like polypeptides (ELPs) and a choline-based bioionic liquid (Bio-IL), providing an electroconductive microenvironment to reconnect damaged nerve tissue. The stretchability akin to native neural tissue was achieved by incorporating hydrophobic ELP pockets, and a robust tissue adhesion was obtained due to multi-mode tissue–material interactions through covalent and noncovalent bonding at the tissue interface. Adhesion tests revealed adhesive strength ~10 times higher than commercially available tissue adhesive, Evicel®. Furthermore, the engineered hydrogel supported in vitro viability and proliferation of human glial cells. We also evaluated the biodegradability and biocompatibility of the engineered bioadhesive in vivo using a rat subcutaneous implantation model, which demonstrated facile tissue infiltration and minimal immune response. The outlined functionalities empower the engineered elastic and electroconductive adhesive hydrogel to effectively enable sutureless surgical sealing of neural injuries and promote tissue regeneration.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 5","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10667","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Given the prevalence of hematological conditions, surgeries, and trauma incidents, hemostats—therapeutics designed to control and arrest bleeding—are an important tool in patient care. The prophylactic and therapeutic use of hemostats markedly enhances survival rates and improves the overall quality of life of patients suffering from these conditions. Since their inception in the 1960s, hemostats have witnessed remarkable progress in terms of the active ingredients utilized, therapeutic outcomes, demonstrated efficacy, and the storage stability. In this review, we provide a comprehensive analysis of commercially available hemostats approved by the FDA, along with newer investigative hemostats currently in active clinical trials. We delve into the modality of active ingredients, route of administration, formulation type, and disease indications of these approved and investigative hemostats. Further, we analyze the trends observed in the hemostat actives for Hemophilia A and B, concluding with insights into the emerging patterns and noteworthy developments to watch for in this dynamic field.
鉴于血液病、手术和创伤事件的普遍性,止血药--用于控制和止血的治疗药物--是病人护理的重要工具。止血钳的预防性和治疗性使用明显提高了患者的存活率,改善了患者的整体生活质量。自 20 世纪 60 年代问世以来,止血药在使用的活性成分、治疗效果、疗效和储存稳定性方面都取得了显著进步。在这篇综述中,我们全面分析了美国食品及药物管理局批准的市售止血剂,以及目前正在进行临床试验的新型研究止血剂。我们深入探讨了这些已获批准的止血药和研究性止血药的活性成分模式、给药途径、制剂类型和疾病适应症。此外,我们还分析了治疗血友病 A 和血友病 B 的止血剂活性成分的发展趋势,最后深入探讨了这一动态领域的新兴模式和值得关注的发展。
{"title":"Hemostats in the clinic","authors":"Maithili Joshi, Zongmin Zhao, Samir Mitragotri","doi":"10.1002/btm2.10673","DOIUrl":"10.1002/btm2.10673","url":null,"abstract":"<p>Given the prevalence of hematological conditions, surgeries, and trauma incidents, hemostats—therapeutics designed to control and arrest bleeding—are an important tool in patient care. The prophylactic and therapeutic use of hemostats markedly enhances survival rates and improves the overall quality of life of patients suffering from these conditions. Since their inception in the 1960s, hemostats have witnessed remarkable progress in terms of the active ingredients utilized, therapeutic outcomes, demonstrated efficacy, and the storage stability. In this review, we provide a comprehensive analysis of commercially available hemostats approved by the FDA, along with newer investigative hemostats currently in active clinical trials. We delve into the modality of active ingredients, route of administration, formulation type, and disease indications of these approved and investigative hemostats. Further, we analyze the trends observed in the hemostat actives for Hemophilia A and B, concluding with insights into the emerging patterns and noteworthy developments to watch for in this dynamic field.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 6","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10673","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew R. Stevens, Mohammed Hadis, Alice Phillips, Abhinav Thareja, Michael Milward, Antonio Belli, William Palin, David J. Davies, Zubair Ahmed
Spinal cord injury (SCI) is a cause of profound and irreversible damage, with no effective therapy to promote functional recovery. Photobiomodulation (PBM) may provide a viable therapeutic approach using red or near-infrared light to promote recovery after SCI by mitigating neuroinflammation and preventing neuronal apoptosis. Our current study aimed to optimize PBM dose regimens and develop and validate the efficacy of an invasive PBM delivery paradigm for SCI. Dose optimization studies were performed using a serum withdrawal model of injury in cultures of primary adult rat dorsal root ganglion neurons (DRGN). Implantable and transcutaneous PBM delivery protocols were developed and validated using cadaveric modeling. The efficacy of PBM in promoting recovery after SCI in vivo was studied in a dorsal column crush injury model of SCI in adult rats. Optimal neuroprotection in vitro was achieved between 4 and 22 mW/cm2. 11 mW/cm2 for 1 min per day (0.66 J/cm2) increased cell viability by 45% over 5 days (p <0.0001), increasing neurite outgrowth by 25% (p <0.01). A method for invasive application of PBM was developed using a diffusion-tipped optogenetics fiber optic. Delivery methods for PBM were developed and validated for both invasive (iPBM) and noninvasive (transcutaneous) (tcPBM) application. iPBM and tcPBM (24 mW/cm2 at spinal cord, 1 min per day (1.44 J/cm2) up to 7 days) increased activation of regeneration-associated protein at 3 days after SCI, increasing GAP43+ axons in DRGN from 18.0% (control) to 41.4% ± 10.5 (iPBM) and 45.8% ± 3.4 (tcPBM) (p <0.05). This corresponded to significant improvements at 6 weeks post-injury in functional locomotor and sensory function recovery (p <0.01), axonal regeneration (p <0.01), and reduced lesion size (p <0.01). Our results demonstrated that PBM achieved a significant therapeutic benefit after SCI, either using iPBM or tcPBM application and can potentially be developed for clinical use in SCI patients.
{"title":"Implantable and transcutaneous photobiomodulation promote neuroregeneration and recovery of lost function after spinal cord injury","authors":"Andrew R. Stevens, Mohammed Hadis, Alice Phillips, Abhinav Thareja, Michael Milward, Antonio Belli, William Palin, David J. Davies, Zubair Ahmed","doi":"10.1002/btm2.10674","DOIUrl":"10.1002/btm2.10674","url":null,"abstract":"<p>Spinal cord injury (SCI) is a cause of profound and irreversible damage, with no effective therapy to promote functional recovery. Photobiomodulation (PBM) may provide a viable therapeutic approach using red or near-infrared light to promote recovery after SCI by mitigating neuroinflammation and preventing neuronal apoptosis. Our current study aimed to optimize PBM dose regimens and develop and validate the efficacy of an invasive PBM delivery paradigm for SCI. Dose optimization studies were performed using a serum withdrawal model of injury in cultures of primary adult rat dorsal root ganglion neurons (DRGN). Implantable and transcutaneous PBM delivery protocols were developed and validated using cadaveric modeling. The efficacy of PBM in promoting recovery after SCI in vivo was studied in a dorsal column crush injury model of SCI in adult rats. Optimal neuroprotection in vitro was achieved between 4 and 22 mW/cm<sup>2</sup>. 11 mW/cm<sup>2</sup> for 1 min per day (0.66 J/cm<sup>2</sup>) increased cell viability by 45% over 5 days (<i>p</i> <0.0001), increasing neurite outgrowth by 25% (<i>p</i> <0.01). A method for invasive application of PBM was developed using a diffusion-tipped optogenetics fiber optic. Delivery methods for PBM were developed and validated for both invasive (iPBM) and noninvasive (transcutaneous) (tcPBM) application. iPBM and tcPBM (24 mW/cm<sup>2</sup> at spinal cord, 1 min per day (1.44 J/cm<sup>2</sup>) up to 7 days) increased activation of regeneration-associated protein at 3 days after SCI, increasing GAP43<sup>+</sup> axons in DRGN from 18.0% (control) to 41.4% ± 10.5 (iPBM) and 45.8% ± 3.4 (tcPBM) (<i>p</i> <0.05). This corresponded to significant improvements at 6 weeks post-injury in functional locomotor and sensory function recovery (<i>p</i> <0.01), axonal regeneration (<i>p</i> <0.01), and reduced lesion size (<i>p</i> <0.01). Our results demonstrated that PBM achieved a significant therapeutic benefit after SCI, either using iPBM or tcPBM application and can potentially be developed for clinical use in SCI patients.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 6","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10674","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140651313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas G. Biel, Talia Faison, Alicia M. Matthews, Uriel Ortega-Rodriguez, Vincent M. Falkowski, Edward Meek, Xin Bush, Matthew Flores, Sarah Johnson, Wells W. Wu, Mari Lehtimaki, Rong-Fong Shen, Cyrus Agarabi, V. Ashutosh Rao, Janice E. Chambers, Tongzhong Ju
Organophosphate (OP) toxicants remain an active threat to public health and to warfighters in the military. Current countermeasures require near immediate administration following OP exposure and are reported to have controversial efficacies. Acetylcholinesterase (AChE) fused to the human immunoglobulin 1 (IgG1) Fc domain (AChE-Fc) is a potential bioscavenger for OP toxicants, but a reproducible AChE-Fc biomanufacturing strategy remains elusive. This report is the first to establish a comprehensive laboratory-scale bioprocessing strategy that can reproducibly produce AChE-Fc and AChE(W86A)-Fc which is a mutated AChE protein with reduced enzymatic activity. Characterization studies revealed that AChE-Fc and AChE(W86A)-Fc are N-glycosylated dimeric fusion glycoproteins but only AChE-Fc had the capability to bind to paraoxon (a model OP). This AChE-Fc fusion glycoprotein bioprocessing strategy can be leveraged during industrial biomanufacturing development, while the research-grade AChE-Fc proteins can be used to determine the potential clinical relevance of the countermeasure against OP toxicants.
有机磷(OP)毒物仍然是对公众健康和军队作战人员的严重威胁。目前的应对措施要求在接触 OP 后几乎立即给药,而且据报道其疗效存在争议。乙酰胆碱酯酶(AChE)与人类免疫球蛋白 1 (IgG1) Fc 结构域融合(AChE-Fc)是一种潜在的 OP 毒性物质生物清除剂,但可重复的 AChE-Fc 生物制造策略仍然难以实现。本报告首次建立了一种全面的实验室规模生物加工策略,可重复生产 AChE-Fc 和 AChE(W86A)-Fc (一种酶活性降低的变异 AChE 蛋白)。表征研究显示,AChE-Fc 和 AChE(W86A)-Fc 是 N-糖基化的二聚体融合糖蛋白,但只有 AChE-Fc 能够与对氧磷(一种 OP 模型)结合。这种 AChE-Fc 融合糖蛋白生物加工策略可在工业生物制造开发过程中加以利用,而研究级 AChE-Fc 蛋白则可用于确定抗 OP 毒物对策的潜在临床相关性。
{"title":"Model acetylcholinesterase-Fc fusion glycoprotein biotechnology system for the manufacture of an organophosphorus toxicant bioscavenging countermeasure","authors":"Thomas G. Biel, Talia Faison, Alicia M. Matthews, Uriel Ortega-Rodriguez, Vincent M. Falkowski, Edward Meek, Xin Bush, Matthew Flores, Sarah Johnson, Wells W. Wu, Mari Lehtimaki, Rong-Fong Shen, Cyrus Agarabi, V. Ashutosh Rao, Janice E. Chambers, Tongzhong Ju","doi":"10.1002/btm2.10666","DOIUrl":"10.1002/btm2.10666","url":null,"abstract":"<p>Organophosphate (OP) toxicants remain an active threat to public health and to warfighters in the military. Current countermeasures require near immediate administration following OP exposure and are reported to have controversial efficacies. Acetylcholinesterase (AChE) fused to the human immunoglobulin 1 (IgG1) Fc domain (AChE-Fc) is a potential bioscavenger for OP toxicants, but a reproducible AChE-Fc biomanufacturing strategy remains elusive. This report is the first to establish a comprehensive laboratory-scale bioprocessing strategy that can reproducibly produce AChE-Fc and AChE(W86A)-Fc which is a mutated AChE protein with reduced enzymatic activity. Characterization studies revealed that AChE-Fc and AChE(W86A)-Fc are <i>N</i>-glycosylated dimeric fusion glycoproteins but only AChE-Fc had the capability to bind to paraoxon (a model OP). This AChE-Fc fusion glycoprotein bioprocessing strategy can be leveraged during industrial biomanufacturing development, while the research-grade AChE-Fc proteins can be used to determine the potential clinical relevance of the countermeasure against OP toxicants.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 5","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10666","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140651637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hao Wu, Jiale Wang, Wenhui Fan, Qi Zhong, Rongyue Xue, Siyu Li, Zongming Song, Ye Tao
Hydrogels are distinguished by their exceptional ability to absorb and retain large volumes of water within their complex three-dimensional polymer networks, which is advantageous for the development of intraocular lenses (IOLs). Their innate hydrophilicity offers an optimal substrate for the fabrication of IOLs that simulate the natural lens' accommodation, thereby reducing irritation and facilitating healing after surgery. The swelling and water retention characteristics of hydrogels contribute to their notable biocompatibility and versatile mechanical properties. However, the clinical application of hydrogels faces challenges, including managing potential adverse postimplantation effects. Rigorous research is essential to ascertain the safety and effectiveness of hydrogels. This review systematically examines the prospects and constraints of hydrogels as innovative materials for IOLs. Our comprehensive analysis examines their inherent properties, various classification strategies, cross-linking processes, and sensitivity to external stimuli. Additionally, we thoroughly evaluate their interactions with ocular tissues, underscoring the potential for hydrogels to be refined into seamless and biologically integrated visual aids. We also discuss the anticipated technological progress and clinical uses of hydrogels in IOL manufacturing. With ongoing technological advancements, the promise of hydrogels is poised to evolve from concept to clinical reality, marking a significant leap forward in ophthalmology characterized by improved patient comfort, enhanced functionality, and reliable safety.
{"title":"Eye of the future: Unlocking the potential utilization of hydrogels in intraocular lenses","authors":"Hao Wu, Jiale Wang, Wenhui Fan, Qi Zhong, Rongyue Xue, Siyu Li, Zongming Song, Ye Tao","doi":"10.1002/btm2.10664","DOIUrl":"10.1002/btm2.10664","url":null,"abstract":"<p>Hydrogels are distinguished by their exceptional ability to absorb and retain large volumes of water within their complex three-dimensional polymer networks, which is advantageous for the development of intraocular lenses (IOLs). Their innate hydrophilicity offers an optimal substrate for the fabrication of IOLs that simulate the natural lens' accommodation, thereby reducing irritation and facilitating healing after surgery. The swelling and water retention characteristics of hydrogels contribute to their notable biocompatibility and versatile mechanical properties. However, the clinical application of hydrogels faces challenges, including managing potential adverse postimplantation effects. Rigorous research is essential to ascertain the safety and effectiveness of hydrogels. This review systematically examines the prospects and constraints of hydrogels as innovative materials for IOLs. Our comprehensive analysis examines their inherent properties, various classification strategies, cross-linking processes, and sensitivity to external stimuli. Additionally, we thoroughly evaluate their interactions with ocular tissues, underscoring the potential for hydrogels to be refined into seamless and biologically integrated visual aids. We also discuss the anticipated technological progress and clinical uses of hydrogels in IOL manufacturing. With ongoing technological advancements, the promise of hydrogels is poised to evolve from concept to clinical reality, marking a significant leap forward in ophthalmology characterized by improved patient comfort, enhanced functionality, and reliable safety.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 5","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10664","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Restoration of extensive tracheal damage remains a significant challenge in respiratory medicine, particularly in instances stemming from conditions like infection, congenital anomalies, or stenosis. The trachea, an essential element of the lower respiratory tract, constitutes a fibrocartilaginous tube spanning approximately 10–12 cm in length. It is characterized by 18 ± 2 tracheal cartilages distributed anterolaterally with the dynamic trachealis muscle located posteriorly. While tracheotomy is a common approach for patients with short-length defects, situations requiring replacement arise when the extent of lesion exceeds 1/2 of the length in adults (or 1/3 in children). Tissue engineering (TE) holds promise in developing biocompatible airway grafts for addressing challenges in tracheal regeneration. Despite the potential, the extensive clinical application of tissue-engineered tracheal substitutes encounters obstacles, including insufficient revascularization, inadequate re-epithelialization, suboptimal mechanical properties, and insufficient durability. These limitations have led to limited success in implementing tissue-engineered tracheal implants in clinical settings. This review provides a comprehensive exploration of historical attempts and lessons learned in the field of tracheal TE, contextualizing the clinical prerequisites and vital criteria for effective tracheal grafts. The manufacturing approaches employed in TE, along with the clinical application of both tissue-engineered and non-tissue-engineered approaches for tracheal reconstruction, are discussed in detail. By offering a holistic view on TE substitutes and their implications for the clinical management of long-segment tracheal lesions, this review aims to contribute to the understanding and advancement of strategies in this critical area of respiratory medicine.
气管大面积损伤的修复仍是呼吸内科面临的一项重大挑战,尤其是在感染、先天畸形或气管狭窄等情况下。气管是下呼吸道的重要组成部分,由纤维软骨组成,长度约为 10-12 厘米。气管的特点是 18±2 根气管软骨分布在气管前侧,动态气管肌位于气管后侧。气管切开术是治疗短缺损患者的常用方法,但当成人的病变范围超过气管长度的 1/2(或儿童的 1/3)时,就需要更换气管。组织工程(TE)有望开发出生物相容性良好的气道移植物,以应对气管再生的挑战。尽管潜力巨大,但组织工程气管替代物的广泛临床应用遇到了障碍,包括血管再生成不足、再上皮化不足、机械性能不理想以及耐久性不足。这些限制导致在临床环境中使用组织工程气管植入物的成功率有限。本综述全面探讨了气管 TE 领域的历史尝试和经验教训,并结合临床先决条件和有效气管移植物的重要标准。详细讨论了气管重建技术中采用的制造方法,以及组织工程和非组织工程气管重建方法的临床应用。通过对 TE 替代物及其对长段气管病变临床治疗的影响提供一个整体的视角,本综述旨在促进对呼吸医学这一关键领域策略的理解和进步。
{"title":"Tissue-engineered tracheal implants: Advancements, challenges, and clinical considerations","authors":"Shixiong Wei, Yiyuan Zhang, Feixiang Luo, Kexing Duan, Mingqian Li, Guoyue Lv","doi":"10.1002/btm2.10671","DOIUrl":"10.1002/btm2.10671","url":null,"abstract":"<p>Restoration of extensive tracheal damage remains a significant challenge in respiratory medicine, particularly in instances stemming from conditions like infection, congenital anomalies, or stenosis. The trachea, an essential element of the lower respiratory tract, constitutes a fibrocartilaginous tube spanning approximately 10–12 cm in length. It is characterized by 18 ± 2 tracheal cartilages distributed anterolaterally with the dynamic trachealis muscle located posteriorly. While tracheotomy is a common approach for patients with short-length defects, situations requiring replacement arise when the extent of lesion exceeds 1/2 of the length in adults (or 1/3 in children). Tissue engineering (TE) holds promise in developing biocompatible airway grafts for addressing challenges in tracheal regeneration. Despite the potential, the extensive clinical application of tissue-engineered tracheal substitutes encounters obstacles, including insufficient revascularization, inadequate re-epithelialization, suboptimal mechanical properties, and insufficient durability. These limitations have led to limited success in implementing tissue-engineered tracheal implants in clinical settings. This review provides a comprehensive exploration of historical attempts and lessons learned in the field of tracheal TE, contextualizing the clinical prerequisites and vital criteria for effective tracheal grafts. The manufacturing approaches employed in TE, along with the clinical application of both tissue-engineered and non-tissue-engineered approaches for tracheal reconstruction, are discussed in detail. By offering a holistic view on TE substitutes and their implications for the clinical management of long-segment tracheal lesions, this review aims to contribute to the understanding and advancement of strategies in this critical area of respiratory medicine.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 4","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10671","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140633935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chemotherapy treatment outcomes are severely restricted by multidrug resistance (MDR), in which tumors develop a multiple cross-resistance toward drug involving the pump and nonpump resistance mechanisms, resulting in drug efflux and defending against drug toxicity. Herein, we constructed a pH and near infrared (NIR) light responsive nanomedicine DOX@FG based on gold nanorods (GNRs) that demonstrated the potential to improve chemotherapy outcomes by overcoming MDR. DOX@FG was constructed by conjugating folic acid (FA) and doxorubicin (DOX) derivatives onto GNRs, where the DOX derivatives possessed an acid-labile hydrazone bond. Stimulated by the acidic media in endocytic organelles, DOX@FG exhibited a responsive dissociation for the controlled release of chemotherapeutic DOX. Surprisingly, we found the mild photothermal effect elicited by GNRs under NIR irradiation simultaneously inhibited the pump and nonpump resistance mechanisms, enhancing the intracellular DOX accumulation and sensitizing the cancer cells to DOX, collectively amplify the chemotherapy efficacy and delay the MCF-7/ADR breast tumor growth. This intelligent DOX@FG nanomedicine with the potential for two-pronged reversal of MDR may provide a prospective way to encourage chemotherapy efficacy.
{"title":"Two-pronged reversal of chemotherapy resistance by gold nanorods induced mild photothermal effect","authors":"Qi Shang, Ziyan Chen, Jing Li, Mingmei Guo, Jiapei Yang, Zhu Jin, Yuanyuan Shen, Shengrong Guo, Feihu Wang","doi":"10.1002/btm2.10670","DOIUrl":"10.1002/btm2.10670","url":null,"abstract":"<p>Chemotherapy treatment outcomes are severely restricted by multidrug resistance (MDR), in which tumors develop a multiple cross-resistance toward drug involving the pump and nonpump resistance mechanisms, resulting in drug efflux and defending against drug toxicity. Herein, we constructed a pH and near infrared (NIR) light responsive nanomedicine DOX@FG based on gold nanorods (GNRs) that demonstrated the potential to improve chemotherapy outcomes by overcoming MDR. DOX@FG was constructed by conjugating folic acid (FA) and doxorubicin (DOX) derivatives onto GNRs, where the DOX derivatives possessed an acid-labile hydrazone bond. Stimulated by the acidic media in endocytic organelles, DOX@FG exhibited a responsive dissociation for the controlled release of chemotherapeutic DOX. Surprisingly, we found the mild photothermal effect elicited by GNRs under NIR irradiation simultaneously inhibited the pump and nonpump resistance mechanisms, enhancing the intracellular DOX accumulation and sensitizing the cancer cells to DOX, collectively amplify the chemotherapy efficacy and delay the MCF-7/ADR breast tumor growth. This intelligent DOX@FG nanomedicine with the potential for two-pronged reversal of MDR may provide a prospective way to encourage chemotherapy efficacy.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 5","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10670","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140620512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer presents a formidable challenge in modern medicine due to the intratumoral heterogeneity and the dynamic microenvironmental niche. Natural or genetically engineered oncolytic bacteria have always been hailed by scientists for their intrinsic tumor-targeting and oncolytic capacities. However, the immunogenicity and low toxicity inevitably constrain their application in clinical practice. When nanomaterials, characterized by distinctive physicochemical properties, are integrated with oncolytic bacteria, they achieve mutually complementary advantages and construct efficient and safe nanobiohybrids. In this review, we initially analyze the merits and drawbacks of conventional tumor therapeutic approaches, followed by a detailed examination of the precise oncolysis mechanisms employed by oncolytic bacteria. Subsequently, we focus on harnessing nanomaterial-assisted oncolytic bacteria (NAOB) to augment the effectiveness of tumor therapy and utilizing them as nanotheranostic agents for imaging-guided tumor treatment. Finally, by summarizing and analyzing the current deficiencies of NAOB, this review provides some innovative directions for developing nanobiohybrids, intending to infuse novel research concepts into the realm of solid tumor therapy.
{"title":"Nanomaterial-assisted oncolytic bacteria in solid tumor diagnosis and therapeutics","authors":"Xiangdi Zeng, Qi Chen, Tingtao Chen","doi":"10.1002/btm2.10672","DOIUrl":"10.1002/btm2.10672","url":null,"abstract":"<p>Cancer presents a formidable challenge in modern medicine due to the intratumoral heterogeneity and the dynamic microenvironmental niche. Natural or genetically engineered oncolytic bacteria have always been hailed by scientists for their intrinsic tumor-targeting and oncolytic capacities. However, the immunogenicity and low toxicity inevitably constrain their application in clinical practice. When nanomaterials, characterized by distinctive physicochemical properties, are integrated with oncolytic bacteria, they achieve mutually complementary advantages and construct efficient and safe nanobiohybrids. In this review, we initially analyze the merits and drawbacks of conventional tumor therapeutic approaches, followed by a detailed examination of the precise oncolysis mechanisms employed by oncolytic bacteria. Subsequently, we focus on harnessing nanomaterial-assisted oncolytic bacteria (NAOB) to augment the effectiveness of tumor therapy and utilizing them as nanotheranostic agents for imaging-guided tumor treatment. Finally, by summarizing and analyzing the current deficiencies of NAOB, this review provides some innovative directions for developing nanobiohybrids, intending to infuse novel research concepts into the realm of solid tumor therapy.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 4","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10672","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140607547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abigail G. Harrell, Stephen R. Thom, C. Wyatt Shields IV
Conventional dogma suggests that decompression sickness (DCS) is caused by nitrogen bubble nucleation in the blood vessels and/or tissues; however, the abundance of bubbles does not correlate with DCS severity. Since immune cells respond to chemical and environmental cues, we hypothesized that the elevated partial pressures of dissolved gases drive aberrant immune cell phenotypes in the alveolar vasculature. To test this hypothesis, we measured immune responses within human lung-on-a-chip devices established with primary alveolar cells and microvascular cells. Devices were pressurized to 1.0 or 3.5 atm and surrounded by normal alveolar air or oxygen-reduced air. Phenotyping of neutrophils, monocytes, and dendritic cells as well as multiplexed ELISA revealed that immune responses occur within 1 h and that normal alveolar air (i.e., hyperbaric oxygen and nitrogen) confer greater immune activation. This work strongly suggests innate immune cell reactions initiated at elevated partial pressures contribute to the etiology of DCS.
{"title":"Dissolved gases from pressure changes in the lungs elicit an immune response in human peripheral blood","authors":"Abigail G. Harrell, Stephen R. Thom, C. Wyatt Shields IV","doi":"10.1002/btm2.10657","DOIUrl":"10.1002/btm2.10657","url":null,"abstract":"<p>Conventional dogma suggests that decompression sickness (DCS) is caused by nitrogen bubble nucleation in the blood vessels and/or tissues; however, the abundance of bubbles does not correlate with DCS severity. Since immune cells respond to chemical and environmental cues, we hypothesized that the elevated partial pressures of dissolved gases drive aberrant immune cell phenotypes in the alveolar vasculature. To test this hypothesis, we measured immune responses within human lung-on-a-chip devices established with primary alveolar cells and microvascular cells. Devices were pressurized to 1.0 or 3.5 atm and surrounded by normal alveolar air or oxygen-reduced air. Phenotyping of neutrophils, monocytes, and dendritic cells as well as multiplexed ELISA revealed that immune responses occur within 1 h and that normal alveolar air (i.e., hyperbaric oxygen and nitrogen) confer greater immune activation. This work strongly suggests innate immune cell reactions initiated at elevated partial pressures contribute to the etiology of DCS.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 5","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10657","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140608106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eric S. Nealy, Steven J. Reed, Steven M. Adelmund, Barry A. Badeau, Jared A. Shadish, Emily J. Girard, Kenneth Brasel, Fiona J. Pakiam, Andrew J. Mhyre, Jason P. Price, Surojit Sarkar, Vandana Kalia, Cole A. DeForest, James M. Olson
Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti-CD47 monoclonal antibodies, when incorporated into subsurface-injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high-grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site-specific modification with hydrolysable “azidoester” adapters, allowing for user-defined release profiles from the hydrogel. Hydrogel-generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8+ T-cells and the attenuation of tumor growth in a “cold” syngeneic melanoma model. This study highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.
{"title":"Versatile tissue-injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics","authors":"Eric S. Nealy, Steven J. Reed, Steven M. Adelmund, Barry A. Badeau, Jared A. Shadish, Emily J. Girard, Kenneth Brasel, Fiona J. Pakiam, Andrew J. Mhyre, Jason P. Price, Surojit Sarkar, Vandana Kalia, Cole A. DeForest, James M. Olson","doi":"10.1002/btm2.10668","DOIUrl":"10.1002/btm2.10668","url":null,"abstract":"<p>Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti-CD47 monoclonal antibodies, when incorporated into subsurface-injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high-grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site-specific modification with hydrolysable “azidoester” adapters, allowing for user-defined release profiles from the hydrogel. Hydrogel-generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8<sup>+</sup> T-cells and the attenuation of tumor growth in a “cold” syngeneic melanoma model. This study highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.</p>","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"9 5","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btm2.10668","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140556639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}