Traumatic spinal cord injury (SCI) disrupts the spinal cord vasculature resulting in ischemia, amplification of the secondary injury cascade and exacerbation of neural tissue loss. Restoring functional integrity of the microvasculature to prevent neural loss and to promote neural repair is an important challenge and opportunity in SCI research. Herein, we summarize the course of vascular injury and repair following SCI and give a comprehensive overview of current experimental therapeutic approaches targeting spinal cord microvasculature to diminish ischemia and thereby facilitate neural repair and regeneration. A systematic review of the published literature on therapeutic approaches to promote vascular repair after experimental SCI was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards. The MEDLINE databases PubMed, Embase, and OVID MEDLINE were searched using the keywords “spinal cord injury,” “angiogenesis,” “angiogenesis inducing agents,” “tissue engineering,” and “rodent subjects.” A total of 111 studies were identified through the search. Five main therapeutic approaches to diminish hypoxia-ischemia and promote vascular repair were identified as (1) the application of angiogenic factors, (2) genetic engineering, (3) physical stimulation, (4) cell transplantation, and (5) biomaterials carrying various factor delivery. There are different therapeutic approaches with the potential to diminish hypoxia-ischemia and promote vascular repair after experimental SCI. Of note, combinatorial approaches using implanted biomaterials and angiogenic factor delivery appear promising for clinical translation.

Platelets and platelet enriched products have been widely studied for their roles in promoting cell proliferation, migration, and tissue regeneration, making them highly interesting for clinical applications such as traumatology, dental, orthopaedic, and plastic surgery. However, their clinical adoption remains limited, partly due to fragmented and inconsistent data. Previous reviews have explored various applications of PRP therapies, but no comprehensive work has systematically mapped their processing methods, treatment modalities, and applications alongside clinical outcomes. This review thus aims to provide a thorough analysis of platelet-rich products, including platelet-rich plasma and platelet lysate, critically assessing their therapeutic potential. Variability in factors such as platelet and leukocyte content, red blood cell contamination, and activation methods complicates the clinical implementation and standardization of platelet-rich products. Herein, we examine platelet structure, function, and growth factors (e.g., PDGF, VEGF, and TGF-β) essential for tissue repair and regeneration, alongside manufacturing processes and isolation techniques impacting product quality. Additionally, we explore platelet recovery, activation strategies (chemical, physical, enzymatic), application forms, patient-related variables, and the immune-modulatory roles of platelets in inflammation, wound healing, and immune response regulation. Our findings highlight the urgent need for standardized protocols to improve consistency and efficacy of platelet-derived products, providing a framework to guide readers in selecting adequate procedures for specific clinical indications or research applications. STATEMENT OF SIGNIFICANCE: Platelet-rich plasma (PRP) has gained widespread attention for its regenerative potential, but its clinical outcomes remain inconsistent due to variability in preparation and application methods. This comprehensive review critically synthesizes the full PRP pipeline-from donor selection and processing to activation strategies and delivery modalities-highlighting key sources of heterogeneity. By integrating current evidence across disciplines, we provide a unified framework for optimizing PRP use in musculoskeletal repair and beyond. This work addresses a major knowledge gap and offers a timely resource for clinicians and researchers aiming to harness PRP more effectively.

Reconstruction of segmental bone defects by autologous bone grafting is still the standard of care but presents challenges including anatomical availability and potential donor site morbidity. The process of 3D bioprinting, the application of 3D printing for direct fabrication of living tissue, opens new possibilities for highly personalized tissue implants, making it an appealing alternative to autologous bone grafts. One of the most crucial hurdles for the clinical application of 3D bioprinting is the choice of a suitable cell source, which should be minimally invasive, with high osteogenic potential, with fast, easy expansion. In this study, mesenchymal progenitor cells were isolated from clinically relevant human bone biopsy sites (explant cultures from alveolar bone, iliac crest and fibula; bone marrow aspirates; and periosteal bone shaving from the mastoid) and 3D bioprinted using projection-based stereolithography. Printed constructs were cultivated for 28 days and analyzed regarding their osteogenic potential by assessing viability, mineralization, and gene expression. While viability levels of all cell sources were comparable over the course of the cultivation, cells obtained by periosteal bone shaving showed higher mineralization of the print matrix, with gene expression data suggesting advanced osteogenic differentiation. These results indicate that periosteum-derived cells represent a highly promising cell source for translational bioprinting of bone tissue given their superior osteogenic potential as well as their minimally invasive obtainability.

Osteoarthritis (OA) most frequently affects the knee joint and is associated with an elevated expression of cytokines and extracellular cartilage matrix (ECM), degrading enzymes such as matrix metalloproteinases (MMPs). Differences in gene expression of the intra-articularly located infrapatellar fat pad (IPFP) and other fatty tissue suggest its autonomous function, yet its role in OA pathogenesis remains unknown. Human IPFPs and articular cartilage were collected from OA patients undergoing total knee arthroplasty, and biopsies from the IPFP of healthy patients harvested during knee arthroscopy served as controls (CO). Isolated chondrocytes were co-cultured with either osteoarthritic (OA) or CO-IPFPs in a transwell system. Chondrocyte expression of MMP1, -3, -13, type 1 and 2 collagens, interleukin IL1β, IL6, IL10, and tumor necrosis factor TNFα was analyzed by RTD-PCR at day 0 and day 2, and TNFα secretion was analyzed by ELISA. The cytokine release in IPFPs was assessed by an array. Results: Both IPFPs (CO, OA) significantly reduced the expression of type 2 collagen and TNFα in chondrocytes. On the other hand, only CO-IPFP suppressed the expression of type 1 collagen and significantly induced the MMP13 expression. On the contrary, IL1β and IL6 were significantly induced when exposed to OA-IPFP. Conclusions: The partial loss of the suppressive effect on type 1 collagen gene expression found for OA-IPFP shows the pathological remodeling and dedifferentiation potential of the OA-IPFP on the chondrocytes. However, the significant suppression of TNFα implies that the OA- and CO-IPFP could also exhibit a protective role in the knee joint, preventing the progress of inflammation.

Background: Chemokine therapy with C–C motif chemokine ligand 25 (CCL25) is currently under investigation as a promising approach to treat articular cartilage degeneration. We developed a delayed release mechanism based on Poly (lactic-co-glycolic acid) (PLGA) microparticle encapsulation for intraarticular injections to ensure prolonged release of therapeutic dosages. However, CCL25 plays an important role in immune cell regulation and inflammatory processes like T-cell homing and chronic tissue inflammation. Therefore, the potential of CCL25 to activate immune cells must be assessed more thoroughly before further translation into clinical practice. The aim of this study was to evaluate the reaction of different immune cell subsets upon stimulation with different dosages of CCL25 in comparison to CCL25 released from PLGA particles. Results: Immune cell subsets were treated for up to 5 days with CCL25 and subsequently analyzed regarding their cytokine secretion, surface marker expression, polarization, and migratory behavior. The CCL25 receptor C–C chemokine receptor type 9 (CCR9) was expressed to a different extent on all immune cell subsets. Direct stimulation of peripheral blood mononuclear cells (PBMCs) with high dosages of CCL25 resulted in strong increases in the secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-1β (IL-1β), tumor-necrosis-factor-α (TNF-α) and interferon-γ (IFN-γ), upregulation of human leukocyte antigen-DR (HLA-DR) on monocytes and CD4⁺ T-cells, as well as immune cell migration along a CCL25 gradient. Immune cell stimulation with the supernatants from CCL25 loaded PLGA microparticles caused moderate increases in MCP-1, IL-8, and IL-1β levels, but no changes in surface marker expression or migration. Both CCL25-loaded and unloaded PLGA microparticles induced an increase in IL-8 and MCP-1 release in PBMCs and macrophages, and a slight shift of the surface marker profile towards the direction of M2-macrophage polarization. Conclusions: While supernatants of CCL25 loaded PLGA microparticles did not provoke strong inflammatory reactions, direct stimulation with CCL25 shows the critical potential to induce global inflammatory activation of human leukocytes at certain concentrations. These findings underline the importance of a safe and reliable release system in a therapeutic setup. Failure of the delivery system could result in strong local and systemic inflammatory reactions that could potentially negate the benefits of chemokine therapy.

Treatment options for critically sized bone defects are currently limited to metal osteosynthesis, autologous bone grafting, or calcium-based implants to bridge the gap. Additive manufacturing techniques pose a possible alternative. The light-basedthree-dimensional printing process of vat photopolymerization (VP) is of particular interest since it enables the printing of complex scaffold architectures at high resolution. This review compares multiple vat photopolymerization processes as well as the employed resin components’ interactions with musculoskeletal cells and tissue. The results show an outstanding printing capability, exceeding the potential of other printing methods. However, despite the availability of various biocompatible materials, neither the mechanical strength of bone nor the scale necessary for clinical application has been achieved so far when relying on single material constructs. One possible solution is the development of adaptive hybrid constructs produced with multimaterial VP.