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Open research questions in Tissue Engineering and Regenerative Medicine

114 gap statements mined from Tissue Engineering and Regenerative Medicine papers in our 4.5M-paper local library, which holds 748 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.

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What the literature leaves open

  • A limitation of the present study inhibitor experiments were not performed to further verify the causal relationship between EGFR pathway activation and the observed therapeutic effects, which will be addressed in our future mechanistic investigations.

    A bioactive heart-derived ECM hydrogel potentiates Astragaloside IV–mediated microvascular regeneration · 2026 · DOI

  • Limited understanding of the interplay between biomaterials, cellular sources, and bioactive signaling. Challenges in creating scaffolds that closely mimic the structural and physicochemical characteristics of the native extracellular matrix. Need for improved clinical translation of tissue engineering technologies.

    Advances and Challenges in Tissue Engineering: Biomaterials, Cellular Strategies, and Clinical Applications · 2026 · DOI

  • The limitations of current basement membrane surrogates, including being derived from murine tumors.

    An animal component-free bioprocess for synthesizing 3D human matrix scaffolds using mesenchymal stromal cells · 2026 · DOI

  • The lack of intrinsic attachment sites for animal cells in alginate-based biomaterials. The need for optimized biofunctional hydrogels for cultivated meat applications. The challenge of developing scalable and sustainable skeletal muscle tissue engineering.

    Peptide screening enables optimised biofunctional hydrogels for cultivated meat tissue engineering · 2026 · DOI

  • Further studies are needed to investigate the role of PNNs in ALS and whether PNN alterations are a primary or secondary effect. Studies should consider the complex interplay between motor neurons and other cell types in ALS. Research should focus on developing therapeutic strategies targeting PNNs in ALS.

    ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons · 2026 · DOI

  • The relevance of PNNs to ALS remains unclear, particularly whether PNN alterations are motor neuron-intrinsic. The extent to which PNN alterations reported in ALS animal models are motor neuron-intrinsic is unknown. The role of PNNs in ALS and whether PNN alterations are a primary or secondary effect is unclear.

    ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons · 2026 · DOI

  • Future directions will center on stimuli-responsive nanosystems, multimodal therapies, organ-on-a-chip models, and sustainable manufacturing. The development of novel high-drug loading capacity nanoparticles is needed. The optimization of targeting efficiency and long-term biosafety is required.

    Nanotechnology-mediated podocyte injury repair: mechanistic exploration and therapeutic prospects · 2026 · DOI

  • Conventional therapies are limited by poor targeting efficacy and systemic side effects. Low drug loading capacity remains a major challenge in the field. Long-term biosafety concerns must be addressed.

    Nanotechnology-mediated podocyte injury repair: mechanistic exploration and therapeutic prospects · 2026 · DOI

  • In contrast to animal studies, there is considerable individual variation in post-infarction cardiac inflammation in clinical settings, and standardized therapeutic strategies are insufficient to meet current clinical needs.

    A closed-loop myocardial infarction theranostic platform activated by macrophage-derived nitric oxide and acidic microenvironment · 2026 · DOI

  • Limited scalability of AT2 expansion methods. Need for a reliable and efficient method for large-scale expansion of AT2s. Limited understanding of the expression of VEGF-A by AT1s and AT2s.

    Leveraging factors that control alveolar epithelial cell fate enables large-scale expansion for lung tissue engineering · 2026 · DOI

  • Building on the mechanistic insights generated in this study, future research will focus on translating these findings toward more physiologically relevant models. A major limitation of this experimental approach is the absence of an immune component.

    Direct Contact with CaHA Microspheres Drives ECM Stimulation In Vitro · 2026 · DOI

  • Challenges related to protocol standardization, long-term clinical validation, regulatory frameworks, and accessibility remain significant barriers to widespread implementation. The study lacks scientific peer review for some excluded studies. Full-text access was unavailable for some excluded studies.

    Advances in Tissue Bioengineering and Regenerative Aesthetic Medicine: Emerging Strategies for Tissue Restoration, Functional Recovery, and Personalized Healthcare · 2026 · DOI

  • There is a need for further research on the clinical applications of regenerative therapies. The study highlights the importance of personalized regenerative approaches that incorporate metabolic and hormonal optimization. There is a lack of standardization in protocols and long-term clinical validation.

    Advances in Tissue Bioengineering and Regenerative Aesthetic Medicine: Emerging Strategies for Tissue Restoration, Functional Recovery, and Personalized Healthcare · 2026 · DOI

  • The lack of cell-type specificity of many immunomodulatory strategies is a major limitation. The discrepancy between in vitro findings and in vivo outcomes is a significant challenge. The complexity and heterogeneity of macrophage biology present significant challenges for the rational design and evaluation of biomaterials-driven strategies.

    Emerging Strategies for Biomaterials-Mediated Reprogramming of Macrophages in Tissue Repair and Regeneration · 2026 · DOI

  • The lack of understanding of macrophage heterogeneity and plasticity during tissue repair. The need for novel strategies to modulate macrophage behavior and enhance tissue repair and regeneration. The limited understanding of the complex interactions between biomaterials and macrophages.

    Emerging Strategies for Biomaterials-Mediated Reprogramming of Macrophages in Tissue Repair and Regeneration · 2026 · DOI

  • Future research should focus on addressing the persistent challenges, including temporal misalignment between scaffold degradation and vessel maturation, unpredictable anastomotic integration with host circulation, and manufacturing scalability limitations.

    Biomimetic hydrogel design strategies for vascular grafts and vascularized tissue constructs · 2026 · DOI

  • Vascular tissue engineering and tissue vascularization share common technical requirements, but there is a lack of integrated analytical frameworks to guide engineering of vascular grafts and tissue constructs.

    Biomimetic hydrogel design strategies for vascular grafts and vascularized tissue constructs · 2026 · DOI

  • A thorough investigation in a follow-up study on whether [(HA-SS)/rhCol III] 18 coating remains effective in promoting the ideal regeneration of the endothelium in a large-animal model of porcine and also in a small-animal pathological cardiovascular model is warranted to ensure its safety and efficacy for future clinical applications.

    Dynamic stiffness enables stage-specific properties mediating functional endothelialization on vascular implants · 2026 · DOI

  • Lack of auto-regulated feedback mechanisms in current therapies. Inability of current platforms to sense and respond to dynamic environmental signals. Need for a new class of auto-regulated and adaptive platforms that can provide context-specific, therapeutic responses.

    Encoded Cell‐Material Interactions to Reroute Cytokine Signaling for Regenerative Medicine · 2026 · DOI

  • A central limitation in developing non-surgical therapies is the incomplete understanding of how cellular remodeling processes drive disease progression and recurrence. The study aims to address this gap by exploring the 3D contractile and remodeling behaviors of human mitral valve interstitial cells from patients with mitral valve prolapse and normal donors.

    3D Contractile and Remodeling Behaviors of Functionally Normal and Prolapsed Human Mitral Valve Interstitial Cells · 2026 · DOI

  • While Chen et al. (2025) demonstrated in vivo efficacy of MSC spheroid-derived 3D decellularized ECM in traumatic brain injury models, the present paper does not include in vivo functional validation of the animal component-free synthesized scaffolds or tissue regeneration capacity in relevant disease models.

    An animal component-free bioprocess for synthesizing 3D human matrix scaffolds using mesenchymal stromal cells · 2026 · DOI

  • Georgi Nikolaev 1,* Radko Sotirov 1,3 and Rossitza Konakchieva 1, Stefan Lozenov 1, Marina Konaktchieva 2, Borislav Arabadzhiev 1, Ivelina Vassileva 1, 1 Department of Cell and Developmental Biology, Faculty of Biology, Sofia University “St.

    Stem Cell Therapies for Gastrointestinal and Liver Diseases: Translational Barriers, Clinical Heterogeneity, and Future Directions · 2026 · DOI

  • Investigation of the long-term viability of the expanded AT2s. Comparison with other AT2 expansion methods. Adaptation of the method for other cell types and applications.

    Leveraging factors that control alveolar epithelial cell fate enables large-scale expansion for lung tissue engineering · 2026 · DOI

  • Future development should focus on several directions: (1) standardized preparation and characterization to reduce variability and improve reproducibility; (2) quantitative potency assays for each product type, such as angiogenic activity for SVF/CEFFE, immunomodulatory capacity for ADSCs, collagen-remodeling ability for ACF, stiffness and retention for AMC, and host-cell infiltration or vascularization potential…

    Hierarchical approaches and regenerative applications of adipose tissue derivatives · 2026 · DOI

  • Treatment is limited to surgical repair or replacement, - Incomplete understanding of how cellular remodeling processes drive disease progression and recurrence, - Small sample size of three patients and three anatomically normal tissue…

    3D Contractile and Remodeling Behaviors of Functionally Normal and Prolapsed Human Mitral Valve Interstitial Cells · 2026 · DOI

Most-cited papers in Tissue Engineering and Regenerative Medicine

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Open questions raised by papers listed on this page include: (1) The lack of intrinsic attachment sites for animal cells in alginate-based biomaterials (“Peptide screening enables optimised biofunctional hydrogels for cultivated meat…”, 2026); (2) Further studies are needed to investigate the role of PNNs in ALS and whether PNN alterations are a primary or secondary effect (“ALS mutations do not alter perineuronal net formation in human stem…”, 2026); (3) The development of novel high-drug loading capacity nanoparticles is needed (“Nanotechnology-mediated podocyte injury repair: mechanistic exploration and…”, 2026); (4) There is a need for further research on the clinical applications of regenerative therapies (“Advances in Tissue Bioengineering and Regenerative Aesthetic Medicine: Emerging…”, 2026); (5) The lack of cell-type specificity of many immunomodulatory strategies is a major limitation (“Emerging Strategies for Biomaterials-Mediated Reprogramming of Macrophages in…”, 2026). 114 gap statements have been mined from Tissue Engineering and Regenerative Medicine papers in our 4.5M-paper local library, which holds 748 papers on the topic; the gaps come from whichever of those papers state one. They are mostly the research gaps the authors state and the papers' abstracts, plus future-work, limitations and challenges passages. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one, so you can read the original claim in context.

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