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Open research questions in Tissue Engineering and Regenerative Medicine

45 unresolved questions extracted from the limitations and future-work sections of 159 Tissue Engineering and Regenerative Medicine papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The development of a theranostic platform that can concurrently sense, quantify, and modulate post-infarction inflammation. The need for a non-invasive method to quantify specific macrophage phenotypes in vivo. The requirement for a pathophysiology-guided approach for the treatment of myocardial infarction.

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

  • Reducing the need for organ transplants - Minimizing rejection syndromes - Improving recovery from trauma, surgery, and chronic damage

    **REGEN-GEL + BIOCAST ORGAN SHIELD SYSTEM** · 2026 · DOI

  • The only treatments available for MVP are replacement or repair; alternative therapies remain elusive due to lack of knowledge of the underlying pathological processes.

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

  • Finally, open challenges in the field are addressed, including translation to clinical applications, and the potential impact of biocompatible engineered nanomaterials and microstructures.

    Engineered nanomaterials and microstructures for tissue engineering and regenerative medicine · 2026 · DOI

  • However, how it affects wound healing and tissue regeneration is still not fully understood.

    Pro-regenerative effects of <i>Cydonia oblonga</i> seed mucilage on endothelial and fibroblast cell models · 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

  • The paper does not address scalability of the xeno-free scaffold synthesis from MSC spheroids to clinically relevant batch sizes or investigate automation and standardization protocols required for therapeutic translation of the decellularized ECM scaffold production.

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

  • The lack of tools to non-invasively quantify specific macrophage phenotypes in vivo. The insufficient standardized therapeutic strategies to meet current clinical needs. The need for a pathophysiology-guided approach for the treatment of myocardial infarction.

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

  • 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

  • There is a critical need to develop effective therapies capable of regenerating damaged heart muscle. The absence of a vascular-like system limits the development of large tissue constructs.

    Three-dimensional culture of heart tissue constructs from heart progenitor cells on a polycaprolactone scaffold - optimization · 2026 · DOI

  • Investigation of the long-term effects of hybrid tissue-engineered vascular grafts; Comparison of the performance of hybrid tissue-engineered vascular grafts with other types of vascular grafts; Evaluation of the safety and efficacy of hybrid tissue-engineered vascular grafts in clinical trials

    From a Biodegradable Scaffold to a Living Artery: Native Arterial Wall Regeneration Following Hybrid Tissue-Engineered Vascular Grafting · 2026 · DOI

  • The lack of a small-diameter vascular graft with long-term patency; The limited capacity for growth and remodeling of currently available prosthetic grafts; The need for a vascular graft that can replicate the multiple biological functions of native vessels

    From a Biodegradable Scaffold to a Living Artery: Native Arterial Wall Regeneration Following Hybrid Tissue-Engineered Vascular Grafting · 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 limited regenerative ability of the adult heart leads to the permanent loss of cardiomyocytes and impairment of cardiac function. Current treatments have limited ability to stimulate tissue-repairing processes and reduce cardiac fibrosis.

    Alginate-gelatin-silk fibroin-containing patches improve cardiac function in an in vivo myocardial infarction murine model · 2026 · DOI

  • The lack of standardization and regulatory pathways for clinical translation. The need for further mechanistic studies on the regenerative mechanisms of adipose tissue derivatives. The limited understanding of the long-term outcomes of using adipose tissue derivatives.

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

  • As a diversified regenerative platform, adipose-derived products include cellular products, cell matrix composites, soluble cell-free extracts, injectable matrix fragments, decellularized scaffolds, and film-like biomaterials. SVF and ADSCs form the cellular foundation; nanofat and SVF-gel preserve stromal cells and ECM components; CEFFE provides a cell-free, paracrine-factor-rich extract; AMC and ACF offer matrix- dominant injectable materials with distinct mechanical and biological properties; and adECM, ADF, and AAF serve as scaffolds and bioactive films. The field is shifting from volume replacement toward mechanism-driven tissue regeneration, and products should be selected according to their dominant functional properties: SVF and ADSCs for angiogenesis, immunomodulation, and paracrine repair; nanofat and SVF-gel for regenerative filling, scar remodeling, and dermal repair; CEFFE for trophic-factor delivery; AMC for structural support; ACF for collagen-rich remodeling; and adECM, ADF, and AAF for scaffold- guided regeneration, wound coverage, tissue expansion, and sustained bioactive delivery. 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 for adECM/ADF/AAF; (3) mechanistic studies using multi-omics, single-cell sequencing, proteomics, spatial transcriptomics, and advanced imaging; (4) engineered delivery systems (hydrogels, microneedles, injectable ECM carriers, 3D-printed scaffolds, and bioactive films) to improve retention, controlled release, and tissue- specific efficacy; and (5) rigorous randomized controlled trials, long-term follow-up, and standardized outcome measures to define safety and efficacy. Looking ahead, adipose-derived products are likely to become indication-specific and modular, enabling combinations of cellular fractions for immune and vascular regulation, soluble extracts for trophic stimulation, collagen-rich matrices for dermal or mechanical support, and acellular scaffolds or films for guided tissue reconstruction. Such strategies may facilitate precise applications in chronic wounds, skin rejuvenation, scar remodeling, soft-tissue reconstruction, tissue expansion, osteoarthritis, ischemic diseases, and peripheral nerve repair. Adipose tissue is no longer merely a passive filler or energy storage, but a rich biological resource for regenerative medicine. The next stage will depend on transforming empirically prepared products into standardized, mechanism-defined, clinically validated, and regulation-compatible therapies. Advances in biomaterials engineering, cell-free therapy, ECM biology, and precision manufacturing will further support personalized and minimally invasive regenerative applications. Page 18 of 23 Han et al. Plast Aesthet Res. 2026;13:20 DECLARATIONS Authors’ contributions Conceptualization, literature search, data synthesis, and drafting of the manuscript: Han T Literature collection, analysis of relevant studies, and manuscript revision: Yang Y Data interpretation, figure and table preparation: Yang H Critical review of the intellectual content and literature verification: Xie Z Literature screening and extraction of key findings: Yan T, Yu Y Assistance with literature organization and referencing: Guo Y Supervision and validation of the review structure: Zhu J, Chen R Conceptualization, overall supervision, and final approval of the version to be published: Yi C Project administration, funding acquisition, and final review: Li H All authors have read and agreed to the published version of the manuscript.

    Hierarchical approaches and regenerative applications of adipose tissue derivatives · 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

  • The reconstruction of functional vascular structures within engineered biomaterials represents a fundamental challenge in regenerative medicine. 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

  • The study does not investigate the long-term effects of the biomimetic coating. The study uses a limited number of animal models. The study does not compare the biomimetic coating to other existing coatings.

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

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45 open questions have been extracted from the limitations and future-work passages of 159 Tissue Engineering and Regenerative Medicine papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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