The first stage of the pipeline tackles a stubborn manufacturing problem. Collagen is the most biologically relevant material for bone scaffolds because it supports cell infiltration, osseointegration, and minimal immune reaction, yet it is notoriously difficult to print directly. Its poor structural stability means that large or irregularly shaped scaffolds tend to collapse under their own weight during printing, forcing researchers to add bulky support structures that must later be discarded. The research team, working across institutions in Germany and Europe, sidestepped this limitation entirely with a hybrid strategy. They 3D-printed a rigid polylactic acid male mold of the desired geometry, cast it in platinum-cured silicone to produce reusable female molds, and then poured rat-tail type I collagen gel into each mold. After lyophilization and cross-linking with glutaraldehyde vapor, the scaffolds emerged with centimeter-scale dimensions, tailored shapes, and sufficient mechanical integrity to spring back to their original form within minutes of being compressed during cell seeding.

This mold-based approach is as much an exercise in sustainability as in engineering. Because the printed molds can be replicated and processed in bulk, the method eliminates the quick-setting photo-crosslinkers and sacrificial support materials that direct bioprinting demands, reducing both material waste and production time. The authors explicitly framed the workflow around the 3R principles of replacement, reduction, and refinement, extending them from animal experimentation into the fabrication process itself. Each silicone mold holds two milliliters of collagen mix, and the resulting scaffolds come in two sections: a broad top section of roughly 0.19 cubic centimeters and a slim bottom section of about 0.10 cubic centimeters, allowing the team to study how geometry influences cell behavior within a single construct.

Before any scaffold could be seeded, the researchers needed a reliable supply of human bone marrow-derived mesenchymal stromal cells, or hMSCs, the workhorses of bone tissue engineering. Conventional culture flasks yield too few cells for large constructs, so the team scaled up expansion in 250-milliliter spinner flasks fitted with rod impellers and CultiSpher-S microcarrier beads. Computational fluid dynamics simulations revealed a linear relationship between stir rate and fluid shear, and identified 90 revolutions per minute as the sweet spot, producing a maximum shear stress of about 7.7 dynes per square centimeter that matched previously optimized conditions in smaller flasks. After twelve days, a single spinner flask yielded an average of 19.28 million cells, compared with only 7.84 million from two conventional T175 flasks, a more than fourfold improvement per vessel. Critically, the cells retained their spindle-like morphology, expressed the stemness markers CD90 and Sox2 at levels comparable to conventionally cultured cells, and passed standard trilineage differentiation assays, confirming that the gentle agitation had not compromised their multipotency.

With cells and scaffolds in hand, the team inoculated each construct with 3.5 million hMSCs, achieving seeding efficiencies of 63.4 percent for pure collagen scaffolds and 73.4 percent for scaffolds embedded with chondroitin sulfate A, a sulfated glycosaminoglycan naturally found in cartilage and bone. CSA is the study’s biochemical masterstroke. Rather than supplementing the culture with exogenous growth factors such as TGF-beta, BMP, IGF, or FGF, which are costly, poorly penetrating in large constructs, and biased toward particular cell types, the researchers embedded CSA directly into the collagen matrix. There it binds and stabilizes growth factors that the cells themselves produce, triggering chondrogenic differentiation. Removing CSA from the medium after fifteen days then allowed the differentiation program to pivot toward osteogenesis, mimicking the sequential choreography of endochondral ossification, the process by which long bones form during development and fracture healing.

The seeded constructs were then encapsulated in agarose bedding inside a perfusion bioreactor, where medium flowed at 5.5 milliliters per minute through hollow channels running parallel to the scaffolds. The agarose serves a dual role: it mimics the connective tissue that envelops native bone and it shields the fragile constructs from excessive fluid shear that would otherwise tear them apart. Fiber-optic oxygen sensors tracked partial oxygen tension at multiple positions over the full sixty days. The medium reservoir held steady at 137.5 millimeters of mercury, and within the constructs themselves, oxygen levels ranged between 58 and 102 millimeters of mercury, an oxygenated niche favorable to osteogenic differentiation. Notably, oxygen tension tracked cell density rather than absolute cell number, and it rose at day thirty when cell counts dipped before falling again as proliferation resumed, demonstrating that the bioreactor maintained a dynamically responsive but consistently oxygenated environment.

The contrast with conventional static culture was stark. After sixty days, constructs grown in the bioreactor retained their original cylindrical dimensions and structural integrity, while statically cultured counterparts shrank dramatically, with pure collagen scaffolds condensing so severely that their bottom sections collapsed. Micro-computed tomography revealed homogeneous mineralization throughout the perfused constructs, with calculated densities reaching up to 175 milligrams per cubic centimeter in collagen scaffolds, whereas static cultures showed dispersed, lower-density mineral deposits. Alizarin red staining confirmed these findings, revealing calcium accumulation in both the inner core and periphery of CSA-containing perfused constructs, while pure collagen constructs showed mineralization only along a thin, compact outer shell surrounding a collapsed interior.

Gene expression analysis told the developmental story in molecular terms. In CSA-containing constructs under perfusion, chondrogenic markers Sox9 and Col2a rose at thirty days, followed by the hypertrophic chondrocyte marker Col10a, and finally the osteoblast markers Runx2, ALP, and Sp7, precisely the sequence expected of endochondral ossification. Pure collagen constructs, by contrast, showed early Sp7 expression with low chondrogenic markers, a pattern consistent with intramembranous ossification, the route that produces compact hard bone directly. The fact that a single population of hMSCs could be steered down either developmental pathway, simply by choosing the scaffold composition and the timing of CSA withdrawal, underscores how much control the platform offers. Osteogenic differentiation was initiated with dexamethasone at one-billionth molar concentration, a hundredfold lower than conventional protocols, further reducing reliance on potent biochemical additives.

The implications extend beyond the laboratory bench. Off-the-shelf bone substitutes could transform treatment for large bone defects from trauma, tumor resection, or spinal fusion, where autologous grafts are limited in supply and carry donor-site morbidity. By demonstrating that large, geometrically tailored, mineralized constructs can be produced sustainably, without growth factor supplementation and with preserved structural integrity over two months of culture, the study establishes a practical baseline for scaling. The authors suggest next steps that include tuning medium pH and oxygen tension, incorporating endothelial cells for vascularization, and validating cell type distribution at the protein level against native bone tissue. They also envision the fluid dynamics model evolving into a digital twin, allowing impeller and flask designs to be optimized computationally before any wet-lab validation. If those refinements succeed, the assembly line described here, from printed mold to perfused, mineralized bone, could become the template for a genuinely industrial approach to regenerative medicine.

Subject of Research: Sustainable biofabrication of tailored collagen-based bone substitutes using scaled stem cell expansion and perfusion bioreactor cultivation

Article Title: Sustainable Fabrication of Tailored Bone Substitutes: From High‐Throughput Scaffold Manufacturing, Scaled‐Up HMSC Expansion to Dynamic Cultivation in a Perfusion Bioreactor

Article References: Braun, F., Paříková, A., Rother, S., Kantor, M., Ilyas, S. M., Bernhardt, R., Yomi, P. N., Havlica, J., Appali, R., Kruppke, B., & Lee, P. S. (2026). Sustainable Fabrication of Tailored Bone Substitutes: From High‐Throughput Scaffold Manufacturing, Scaled‐Up HMSC Expansion to Dynamic Cultivation in a Perfusion Bioreactor. Advanced Science, 13(56), Article e23846. https://doi.org/10.1002/advs.202523846

Image Credits: AI Generated

DOI: 10.1002/advs.202523846

Keywords: bone tissue engineering, collagen scaffolds, 3D printing, hMSCs, perfusion bioreactor, chondroitin sulfate A, endochondral ossification, spinner flask, mineralization, growth factors, sustainable fabrication, regenerative medicine

The review, led by Seung-Jae Lee of the Korea Research Institute of Bioscience and Biotechnology, synthesizes decades of research into the biochemical composition of deer antler velvet, commonly abbreviated DAV. The tissue is a biochemical treasure chest: it contains abundant type I and type II collagen, a broad spectrum of bioactive peptides, and an impressive array of growth factors including insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), transforming growth factor-beta (TGF-β), and several fibroblast growth factors. Alongside these sit glycosaminoglycans such as chondroitin sulfate and hyaluronic acid, essential and non-essential amino acids, minerals including calcium, phosphorus, magnesium, zinc, and iron, phospholipids, gangliosides, polysaccharides, nucleotides, and sialic acid. Each of these compound classes has documented biological activity in laboratory settings, which explains why DAV has attracted attention for applications ranging from joint health to neuroprotection.

The mechanistic story emerging from preclinical research is coherent, at least on paper. Growth factors found in DAV are known to engage canonical signaling cascades such as PI3K/Akt, MAPK/ERK, and JAK/STAT, pathways that govern cell proliferation, extracellular matrix synthesis, and tissue remodeling. In cell culture and animal models, DAV-derived fractions have been shown to stimulate osteoblast proliferation, promote chondrogenesis, accelerate wound closure, and support angiogenesis. Meanwhile, DAV peptides and polysaccharides appear to modulate redox balance by upregulating antioxidant enzymes like superoxide dismutase, catalase, and glutathione peroxidase, and to suppress inflammation through inhibition of the NF-κB pathway and modulation of MAPK signaling, reducing pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β while boosting the anti-inflammatory mediator IL-10. Gangliosides and phospholipids in the tissue have been linked to neuronal survival and synaptic plasticity, and rodent studies report improvements in learning and memory as well as protection against chemically induced neuronal damage.

But here is where the review delivers its most sobering message: biological plausibility is not clinical proof. The overwhelming majority of the evidence for DAV’s celebrated effects comes from in vitro experiments and animal models, with comparatively few well-controlled human trials. One of the few clinical studies examining physical performance, conducted with just 38 participants, produced outcomes that were not entirely consistent, and its small sample size limits statistical power and generalizability. Systematic reviews of randomized controlled studies of deer and elk velvet antler supplements have similarly found the human evidence base thin and heterogeneous. For conditions such as osteoporosis, cartilage degeneration, neurodegenerative disease, or chronic inflammation, no large-scale randomized controlled trials with clinically meaningful endpoints currently exist.

A deeper problem lurks beneath the evidence gap: the question of bioavailability. The star molecules of DAV, particularly IGF-1 and other peptide growth factors, are proteins, and proteins face a hostile journey through the human gastrointestinal tract, where digestive enzymes typically cleave them into fragments long before they could reach systemic circulation intact. The review emphasizes that the extent to which intact growth factors survive digestion and achieve physiologically relevant concentrations in the bloodstream remains fundamentally uncertain. This means that some observed biological effects may actually reflect smaller peptide fragments or indirect signaling modulation rather than direct systemic growth factor activity. Encapsulation, protective co-formulation, and controlled-release delivery systems are being explored to improve stability and absorption, but comprehensive pharmacokinetic data on DAV-derived growth factors in humans remain scarce.

Compounding the bioavailability problem is the issue of standardization. Deer antler velvet is not a single, uniform substance. Its composition varies with species, the age of the animal, the stage of antler growth at harvest, diet, seasonal factors, and processing methods. Hot water extraction, the most common traditional approach, effectively solubilizes proteins, peptides, and polysaccharides but can partially denature heat-sensitive growth factors. Ethanol extraction enriches lipid-soluble compounds but may reduce overall protein content. Modern techniques such as enzymatic hydrolysis, ultrasonic-assisted extraction, and supercritical CO₂ extraction offer improved yields and selectivity, with enzymatically hydrolyzed preparations showing higher immunomodulatory and osteogenic activity in some studies. Yet even with these advances, batch-to-batch reproducibility remains elusive, and internationally harmonized quality standards for DAV do not yet exist. Analytical tools including high-performance liquid chromatography, ELISA, and mass spectrometry are available for compositional profiling, but no universally accepted marker compounds have been established.

Safety data, while generally reassuring, carry their own caveats. Toxicological assessments in rodents report low acute and subchronic toxicity, with minimal adverse effects on liver and kidney function, hematological parameters, and behavior even at relatively high doses. However, long-term studies covering reproductive toxicity, carcinogenicity, and large-scale human safety are limited. The presence of growth-promoting molecules raises theoretical endocrine and oncogenic concerns, even though conventional DAV supplementation has not been conclusively associated with such adverse outcomes in humans. Allergenicity is biologically plausible given the tissue’s protein content, though documented severe allergic responses appear uncommon. The review also notes that growth-associated factors have attracted attention in athletic contexts regarding anti-doping compliance, although current evidence does not clearly demonstrate supraphysiological systemic effects from oral consumption.

The regulatory landscape is equally fragmented. In China and Korea, DAV is embedded within traditional medicinal systems and functional product frameworks, while in the United States and the European Union it is typically classified as a dietary supplement or natural health product subject to good manufacturing practices and restricted health claims. This patchwork of classifications, combined with compositional variability, creates a regulatory bottleneck: without quantified, reproducible marker compounds such as defined peptide fractions or measured IGF-1 levels, dose standardization and cross-border market integration remain difficult. Ethical considerations, including sustainable harvesting practices and animal welfare, are also increasingly shaping consumer acceptance and regulatory review.

What would it take for deer antler velvet to move from traditional remedy and speculative supplement to evidence-based therapeutic or functional ingredient? The review lays out a clear roadmap. First, researchers must establish defined compositional markers or fingerprints that correlate with biological activity, supported by validated analytical methods and bioassay-guided standardization. Second, rigorous pharmacokinetic and bioavailability studies are needed to determine which components, if any, reach systemic circulation in active form and at what doses. Third, well-powered randomized controlled trials evaluating clinically meaningful endpoints, rather than surrogate biomarkers, must be conducted with standardized formulations. Fourth, regulatory frameworks need harmonization grounded in reproducible quality control and transparent labeling. Technological innovations in extraction, stabilization, and delivery may help, but the authors caution that these must be accompanied by rigorous comparative evaluation rather than assumed improvements.

The broader lesson of the DAV story extends beyond a single ingredient. It illustrates a pattern familiar from many traditional natural products: a rich biochemical composition and compelling mechanistic plausibility that outpace the clinical evidence needed to justify health claims. Deer antler velvet genuinely contains molecules that regulate growth, redox balance, immune signaling, and tissue remodeling, and its intrinsic regenerative biology remains a fascinating model for studying angiogenesis, mineralization, and stem cell dynamics. But as the review’s authors conclude, the future of DAV in biomedical and nutraceutical applications will depend not on expanding the list of proposed benefits, but on deepening the validation behind each one. Until standardized compositions, pharmacokinetic clarity, and robust human trials arrive, consumers and clinicians alike should view this ancient remedy with informed, measured skepticism, appreciating its biological promise while recognizing how much rigorous science remains to be done.

Subject of Research: Bioactive composition, mechanisms, and translational challenges of deer antler velvet for biomedical and nutraceutical applications

Article Title: Deer antler velvet as a multifunctional natural resource for biomedical and nutraceutical applications

Article References: Lee, S.-J., Bak, S. G., Cheon, Y. J., Chandimali, N., & Bae, J. (2026). Deer antler velvet as a multifunctional natural resource for biomedical and nutraceutical applications. Food Science of Animal Resources, 46(1), Article 54. https://doi.org/10.1007/s44463-026-00070-z

Image Credits: AI Generated

DOI: 10.1007/s44463-026-00070-z

Keywords: deer antler velvet, IGF-1, growth factors, nutraceuticals, collagen, bioavailability, standardization, regenerative medicine, immunomodulation, antioxidant, functional foods, clinical trials

The chemistry behind this promise is striking. Immunoglobulins, chiefly IgG, make up roughly 70 to 80 percent of the total protein in first-day colostrum, and their concentration can reach 50 to 100 milligrams per milliliter in the first days after delivery, orders of magnitude above the levels found in mature milk. Total protein in day-one colostrum approaches 15 percent by weight before falling to around 3 percent within days. Alongside the antibodies sit lactoferrin, an iron-binding glycoprotein with antibacterial, antiviral and anti-inflammatory activity; lactoperoxidase, an enzyme that generates reactive compounds lethal to a broad range of bacteria; and growth factors such as IGF-1 and TGF-beta that drive epithelial repair and tissue regeneration. Proline-rich polypeptides add a further layer of immune regulation, capable of damping down overactive responses of the kind seen in allergy and autoimmunity.

What makes bovine colostrum particularly attractive compared with colostrum from other species is a combination of potency, abundance and cross-species compatibility. The IgG concentration in bovine colostrum is nearly 100 times higher than in human colostrum, and many of its bioactive molecular structures are conserved across mammals, allowing bovine-derived molecules to interact effectively with human receptors. Dairy cows also produce far more colostrum than a calf can consume, creating a renewable surplus that can be harvested without compromising animal welfare. Regulatory agencies in several countries already recognize bovine colostrum as a generally safe natural nutraceutical ingredient, and its production is scalable in a way that human, goat or camel colostrum simply is not.

The carbohydrate fraction of colostrum is proving equally interesting. Bovine colostrum contains between 0.7 and 1.2 milligrams per milliliter of oligosaccharides, the majority of them acidic, sialylated structures such as 3′-sialyllactose, which accounts for about 70 percent of the total. Forty distinct oligosaccharide compositions have been identified so far, and their levels peak immediately after parturition before declining within 48 hours. Unlike the predominantly fucosylated oligosaccharides of human milk, bovine milk oligosaccharides are mostly sialylated, and recent advances in enzymatic glycosylation are making it possible to modify their structures to resemble human milk oligosaccharides more closely. Glycoproteins such as the casein-derived glycomacropeptide add prebiotic value, promoting the growth of beneficial Bifidobacterium in the gut.

Turning this perishable fluid into a stable commercial ingredient is a technological challenge in its own right, and the review devotes considerable attention to processing science. Freeze-drying, or lyophilization, is described as the gold standard: by freezing colostrum and removing water through sublimation under reduced pressure, the process avoids the heat that would denature thermolabile proteins. Freeze-dried colostrum retains 85 to 95 percent of original IgG activity, and with cryoprotectants such as trehalose or maltodextrin, probiotic survival rates of 80 to 90 percent can be achieved. Spray-drying, by contrast, is the workhorse of industrial production, atomizing liquid colostrum into hot air at inlet temperatures of 140 to 180 degrees Celsius. Although somewhat harsher, optimized spray-drying can still preserve 70 to 80 percent of immunoglobulin activity while dramatically reducing microbial load and extending shelf life, which is why it remains the method of choice for large-scale manufacturing.

Clinical evidence is accumulating across a surprising range of conditions. In gastrointestinal medicine, colostrum has shown benefit in irritable bowel syndrome, ulcerative colitis and infectious diarrhea. A small pilot trial of a colostrum enema in ulcerative colitis saw symptom improvement in seven of eight treated patients, and hyperimmune colostrum tablets targeting enterotoxigenic E. coli provided roughly 90 percent protection against experimentally induced traveler’s diarrhea in challenge studies. Perhaps most striking is the interaction with painkillers: in a crossover trial, volunteers taking the NSAID indomethacin alongside whey protein saw intestinal permeability rise nearly threefold, whereas those co-administered bovine colostrum showed no significant increase at all, an effect attributed to growth factors that promote healing of the gut lining.

Athletes form another key target population. The first study of colostrum supplementation in sport, published in 1997, reported increases in serum immunoglobulin concentrations and explosive muscular power. Subsequent controlled trials have found improvements in lean body mass, cycling performance and recovery in runners, and one study of older adults undergoing resistance training showed enhanced leg press strength and reduced bone resorption at a dose of 60 grams per day. Supplementation has also been linked to reduced exercise-induced gut permeability and, in some studies, elevated secretory IgA in saliva, although these immune findings have not always been replicated. Researchers caution that the mechanisms remain unclear and that the effects probably cannot be explained by protein content alone, since whey protein controls with matching protein levels generally perform less well.

The newest frontier comes from omics technologies. Proteomic profiling has identified more than a thousand distinct proteins and peptides in bovine colostrum, revealing low-abundance bioactives such as osteopontin, milk fat globule membrane proteins and lactoperoxidase that participate in immune signaling, mucosal defense and tissue repair. Even more provocative is the discovery of microRNAs packaged within stable extracellular vesicles. These small regulatory RNAs, including miR-148a and miR-21, appear capable of surviving passage through the digestive tract and influencing gene expression in recipient cells, modulating T-cell differentiation, macrophage activation and the integrity of tight junctions in the intestinal barrier. Some evidence suggests these molecules may even cross species barriers, adding an epigenetic dimension to colostrum’s bioactivity that extends well beyond its traditional protein and peptide mechanisms.

The review is careful to balance enthusiasm with caution. Colostrum’s bioactive content varies substantially between batches depending on breed, diet, parity and collection time, raising standardization and labeling concerns in loosely regulated markets. Milk protein allergy and lactose intolerance remain relevant risks for sensitive individuals, and fresh colostrum is highly perishable and prone to contamination with pathogens such as E. coli, Salmonella and Listeria unless properly pasteurized or dried. Theoretical questions also persist about long-term exposure to concentrated growth factors, particularly for people with hormone-sensitive conditions, and the authors call for larger, well-designed, double-blind and placebo-controlled trials to confirm many of the reported clinical benefits.

Nevertheless, the overall trajectory is unmistakable. From functional foods and infant nutrition to sports supplements and pharmaceutical formulations, bovine colostrum is being repositioned as a multifunctional bioactive matrix rather than a simple dairy byproduct. New encapsulation and delivery systems are being developed to improve the bioavailability and targeting of its fragile components, and metabolomic and transcriptomic studies continue to uncover candidates with antiviral and immunomodulatory potential. As consumer demand shifts toward natural products with immune-enhancing and regenerative properties, the review concludes that this ancient first milk, once valued only for the survival of newborn calves, may become a staple ingredient of future functional nutrition and therapeutic development, provided that quality control, sustainable sourcing and processing standardization keep pace with the science.

Subject of Research: Nutritional composition, bioactive components and therapeutic applications of bovine colostrum

Article Title: Health benefits and value addition of bovine colostrum (BC): a comprehensive review of its nutritional and functional potential

Article References: Riaz, S., Imran, A., Rasheed, M., Amjad, A., Shankar, A., Chauhan, G., Basharat, Z., Islam, F., Naeem, U., & Ndagire, C. T. (2026). Health benefits and value addition of bovine colostrum (BC): a comprehensive review of its nutritional and functional potential. Food Science of Animal Resources, 46(1), Article 55. https://doi.org/10.1007/s44463-026-00057-w

Image Credits: AI Generated

DOI: 10.1007/s44463-026-00057-w

Keywords: bovine colostrum, immunoglobulins, lactoferrin, growth factors, gut health, functional foods, nutraceuticals, freeze-drying, spray-drying, microRNAs, immune modulation, sports nutrition

The biological story at the heart of the review unfolds in four overlapping stages: hemostasis, inflammation, proliferation, and remodeling. Within seconds of injury, platelets aggregate and form a fibrin clot that stops blood loss and simultaneously releases an early burst of chemical signals. The review emphasizes that this initial clot is far more than a plug; it is a temporary scaffold soaked in platelet-derived growth factor and transforming growth factor beta, the molecules that recruit neutrophils and macrophages into the wound bed. Neutrophils arrive first, engulfing bacteria and releasing antimicrobial compounds, and recent work on neutrophil extracellular traps, web-like structures of DNA and toxic proteins that immobilize pathogens, illustrates how these cells shape the wound environment in ways that can either clear infection or, when excessive, damage surrounding tissue and prolong inflammation.

As inflammation gives way to proliferation, the cast of molecular players expands. The review catalogues the major growth factors and their receptors: vascular endothelial growth factor driving new blood vessel formation, epidermal growth factor and fibroblast growth factor stimulating keratinocyte and fibroblast division, and platelet-derived growth factor sustaining the migration of repair cells into the defect. These ligands feed into a remarkably interconnected web of intracellular signaling cascades, including SMAD, MAPK, PI3K/AKT, JAK/STAT, Wnt/beta-catenin, Notch, Hippo/YAP-TAZ, mTOR, and NF-kappaB pathways. The authors stress that no single pathway acts alone; transforming growth factor beta, for example, orchestrates both early inflammation and later scar formation through SMAD-dependent transcription, while hypoxia within the wound modifies how fibroblasts respond to its isoforms, linking oxygen tension directly to the quality of the matrix they deposit.

The extracellular matrix emerges in the review as far more than passive scaffolding. Collagen fibers, glycoproteins such as fibronectin and laminin, and bridging molecules like nidogen and perlecan form the basement membrane that underpins epidermal integrity, and their organization determines whether tissue regains strength or fails structurally. Specialized fibroblasts differentiate into myofibroblasts, the contractile cells that pull wound edges together, and their secretome interacts dynamically with the surrounding microenvironment. Single-cell RNA sequencing studies cited in the review reveal that fibroblasts in diabetic wounds are not a uniform population but a heterogeneous collection of subtypes, some of which appear locked into dysfunctional states. This heterogeneity helps explain why diabetic ulcers so often stall in a chronic, inflammatory phase and why therapies that work in acute wounds frequently disappoint in chronic ones.

Chronic wound biology occupies a central place in the analysis. In diabetes, persistently elevated pro-inflammatory cytokines disrupt the normal transition from the inflammatory to the proliferative phase, leaving wounds trapped in a self-perpetuating cycle of tissue destruction and incomplete repair. Microbial biofilms add another layer of complexity: structured bacterial communities encased in protective matrix resist both antibiotics and immune cells, and the review highlights recent work framing biofilms as major diagnostic and therapeutic barriers in non-healing wounds. Hypertrophic scarring and keloids represent the opposite failure mode, in which fibroblast activity and collagen deposition overshoot, producing raised, disfiguring lesions whose molecular pathogenesis, from altered growth factor signaling to mechanical tension, is now being mapped in detail. The review also notes the underappreciated symptom burden of chronic wounds, including the prevalence and mechanisms of itch, which affects quality of life in ways clinical metrics often overlook.

Against this molecular backdrop, the review turns to traditional and indigenous therapies, and this is where the narrative becomes genuinely striking. Honey, one of the oldest wound dressings known to medicine, receives the strongest evidential endorsement. A Cochrane systematic review on honey as a topical wound treatment, alongside more recent systematic reviews and meta-analyses of honey in diabetic foot ulcers, supports its antibacterial and healing-promoting properties, which are attributed to high osmolarity, acidity, hydrogen peroxide generation, and additional bioactive compounds. The authors point out that honey has effectively migrated from folk remedy to advanced wound care product, with medical-grade formulations now used in clinical settings worldwide.

Aloe vera is another traditional remedy with growing mechanistic support. Studies cited in the review show that aloe gel extracts promote fibroblast proliferation, migration, and viability, and that its phenolic and polysaccharide fractions contribute to wound-healing activity in vitro. The review also surveys a wide ethnobotanical landscape: Moringa oleifera fractions tested in human dermal fibroblasts, Vietnamese medicinal plants with documented traditional wound uses, Croton species from South American traditional medicine, Justicia pectoralis, prickly pear cactus, ash species from Caucasus ethnobotany, and neem oil, whose acute and subacute toxicity has been formally evaluated. Animal-derived remedies appear as well, including frog skin preparations and the antibacterial peptides discovered in frog skin secretions, such as dermaseptin-AC from the red-eyed tree frog Agalychnis callidryas, a molecule identified and rationally designed as a novel antimicrobial agent.

Perhaps the most vivid example of tradition validated by modern evidence is maggot debridement therapy, the controlled application of fly larvae to clean necrotic tissue from chronic wounds. A systematic review of maggot therapy in wound healing supports its role in removing dead tissue and controlling infection, and the review notes that some of these traditional treatments are now backed by Cochrane review-level evidence, the gold standard in evidence-based medicine. The authors also flag the ethical dimension of this research frontier: the Nagoya Protocol on access to genetic resources establishes the framework for fair and equitable benefit-sharing when indigenous knowledge and biological resources feed into commercial drug development, a reminder that translating traditional medicine into modern therapeutics carries obligations to the communities that preserved that knowledge.

The review situates these traditional approaches within the broader arc of modern wound care technology. Smart dressings that respond to the wound environment, collagen-based products, curcumin-loaded drug delivery systems for acute and chronic wounds, mesenchymal stem cell-derived exosomes, and bioengineered skin substitutes all feature in the cited literature as the field moves from passive coverage toward active, biology-directed intervention. Specialized pro-resolving lipid mediators and dietary omega-3 and omega-6 fatty acids represent another emerging strategy, aiming not to suppress inflammation but to actively resolve it, a concept that reframes chronic wounds as failures of resolution rather than simply failures of defense.

The authors’ conclusion is ultimately a call for integration. By connecting the molecular pathways that regulate each phase of repair, the cellular dysfunctions that trap wounds in chronicity, the newest biological therapies, and the evidence-based subset of traditional medicine, they argue, researchers can chart a path toward safer and more effective wound treatment. In an era when antimicrobial resistance threatens conventional approaches and diabetic wounds continue to consume enormous healthcare resources, the idea that a molecule from frog skin, a polysaccharide from aloe, or medical-grade honey might stand alongside growth factor therapeutics and engineered dressings is no longer fringe science. It is, the review suggests, exactly the kind of cross-disciplinary synthesis that chronic wound care has been waiting for, provided the evidence is gathered as rigorously as the molecular biology itself.

Subject of Research: The molecular mechanisms of skin wound healing and the evidence base for indigenous and traditional wound therapies

Article Title: An integrative review of wound healing: anatomy, molecular mediators, and indigenous therapies

Article References: Dhanush, R., Naveen, D. K., Sneha, H. R., Mudhol, S., & Raghunathanaidu, B. D. (2026). An integrative review of wound healing: anatomy, molecular mediators, and indigenous therapies. Molecular Biology Reports, 53(1), Article 1663. https://doi.org/10.1007/s11033-026-12835-2

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12835-2

Keywords: wound healing, growth factors, signaling pathways, chronic wounds, honey, Aloe vera, maggot debridement therapy, traditional medicine, indigenous therapies, extracellular matrix, biofilms, diabetic foot ulcers