Bioengineering & Translational Medicine最新文献

Confounding results of engineered mesenchymal stem cells (MSCs) used as cellular vehicles has plagued technologies whereby success or failure of novel approaches may be dismissed or inaccurately ascribed solely to the biotechnology platform rather than suitability of the human donor. Polymeric materials were screened for non-viral engineering of MSCs from multiple human donors to deliver bone morphogenic protein-4 (BMP4), a protein previously investigated in clinical trials for glioblastoma (GBM) to combat a subpopulation of highly invasive and tumorigenic clones. A “smart technology” that target the migratory and stem-like nature of GBM will require: (1) a cellular vehicle (MSC) which can scavenge and target residual cells left behind after surgical debulking and deliver; (2) anti-glioma cargo (BMP4). Multiple MSC donors are safely engineered, though varied in susceptibility to accept BMP4 due to intrinsic characteristics revealed by their molecular signatures. Efficiency is compared via secretion, downstream signaling, differentiation, and anti-proliferative properties across all donors. In a clinically relevant resection and recurrence model of patient-derived human GBM, we demonstrate that nanoengineered MSCs are not “donor agnostic” and efficacy is influenced by the inherent suitability of the MSC to the cargo. Therefore, donor profiles hold greater influence in determining downstream outcomes than the technical capabilities of the engineering technology.

Antibody-drug conjugates (ADCs), chemotherapeutic agents conjugated to an antibody to enhance their targeted delivery to tumors, represent a significant advancement in cancer therapy. ADCs combine the precise targeting capabilities of antibodies and the potent cell-killing effects of chemotherapy, allowing for enhanced cytotoxicity to tumors while minimizing damage to healthy tissues. Here, we provide an overview of the current clinical landscape of ADCs, highlighting 11 U.S. Food and Drug Administration (FDA)-approved products and discussing over 500 active clinical trials investigating newer ADCs. We also discuss some key challenges associated with the clinical translation of ADCs and highlight emerging strategies to overcome these hurdles. Our discussions will provide useful guidelines for the future development of safer and more effective ADCs for a broader range of indications.

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.

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.

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.

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.

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.

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.

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.

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.