Collagen-Based Products in Wound, Skin, and Health Care

Abstract

Collagen, the most abundant structural protein in the human body, plays a vital role in wound healing, tissue repair, and skin integrity. Collagen-based products—ranging from wound dressings, skin substitutes, dental and orthopedic scaffolds, to topical cosmetics and oral supplements—have proliferated rapidly across healthcare and consumer markets. Medical applications leverage collagen’s biocompatibility, biodegradability, and scaffold-forming properties to manage chronic wounds, burns, and bone defects, while emerging technologies such as recombinant collagen and phage-integrated dressings target future innovations. Topical collagen improves skin hydration but is unlikely to replace endogenous collagen; injectable fillers offer temporary cosmetic enhancement with some potential risks. Oral collagen supplements, although marketed for skin, joint, and hair health, primarily serve as incomplete proteins and require cautious interpretation, as rigorous clinical evidence supporting transformative outcomes remains limited. Specific formulations such as undenatured type II collagen show promise for inflammatory joint conditions by promoting immune tolerance. In wound care, collagen-based scaffolds enhance healing by supporting fibroblast proliferation, reducing inflammation, and modulating moisture balance, while novel crosslinked matrices and living skin equivalents push regenerative medicine boundaries. Not all collagen-based products are the same. As the global collagen market surges toward $18.7 billion by 2030, users must distinguish between marketing claims and evidence-based benefits of specific preparations. Proper product selection should be guided by clinical context, molecular source (animal, marine, recombinant), and intended use with awareness of underlying scientific evidence critical to therapeutic success. Continued innovation, rigorous validation, mechanism of action studies and rigorous clinical testing are essential to fully realize collagen’s therapeutic potential across medicine and wellness.

SCOPE AND SIGNIFICANCE

This article provides an overview of collagen-based products spanning wound care, skin health, regenerative medicine, orthopedics, dentistry, and consumer wellness. It critically examines collagen’s biomaterial properties—biocompatibility, biodegradability, and scaffold-forming capacity—that underpin its widespread applications. Common collagen-based products are systematically categorized based on scientific levels of evidence, offering users an evidence-based framework to navigate a rapidly expanding market. The work highlights emerging innovations such as recombinant collagen, 3D-printed skin grafts, and phage-integrated dressings, while cautioning against unsupported marketing claims. This work is not intended to be a systematic review. This is specifically a critical review (note peer-review process in Acknowledgments). While briefly noting key milestones in product development, the focus remains on technological trends, biomolecular sources, and functional advances. Projected to drive a $18.7 billion global market by 2030, collagen’s future hinges on rigorous validation, innovation, and responsible translation.¹ Serving health care providers, researchers, manufacturers, and informed consumers alike, this article delivers a critical, science-grounded roadmap to understanding collagen’s evolving impact across medical, cosmetic, and biotechnology sectors.

TRANSLATIONAL RELEVANCE

Collagen, the dominant structural protein in the human body (25–30% of total body protein), has been incorporated into a multitude of medical devices designed for wound healing, tissue regeneration, and skin care. Collagen can easily be isolated from animal, plant and marine sources, as well as be produced in a laboratory synthetically or as recombinant protein (Fig. 1). The abundant accessibility and ease of use in clinical applications has led to a global market of patient-accessible products that promote positive healing outcomes compared with more traditional approaches.

Figure 1.

Collagen sources. Collagen is a protein abundantly available from a variety of sources. Collagen can easily be isolated from animal, plant, and marine sources. Collagens can also be produced in a laboratory synthetically or as yeast/fermentation-derived recombinant protein.

CLINICAL RELEVANCE

This article delivers critical insights for health care providers utilizing collagen-based products in clinical and wellness practice. It sketches the biological roles of collagen in wound healing, skin regeneration, orthopedic repair, and dental reconstruction, emphasizing how product-specific properties—such as molecular structure, source, crosslinking, and bioactivity—affect clinical outcomes. By categorizing commonly used collagen products according to levels of scientific evidence, the work offers an essential guide for evidence-based product selection. It highlights the importance of matching the product’s mechanism of action—such as scaffold support, moisture balance, matrix metalloproteinase inhibition, or antimicrobial enhancement—to the patient’s wound type and healing phase. Furthermore, it addresses emerging challenges such as biofilm resistance, impaired vascularization, and chronic wound recurrence, suggesting collagen innovations that may overcome these barriers. Health care providers are encouraged to critically evaluate marketing claims, understand product-specific risks, and prioritize products validated by rigorous clinical trials to optimize patient outcomes.

WOUND HEALING AND CARE

Collagen is the most abundant protein in the human body (25–30% total protein). There are at least 28 types of collagens of which over 90% of the collagen in humans is type I & III. Collagen-based products have proven beneficial, with utility spanning a range of products from medical devices to cosmetic and food applications. In 1981, Collagen Corporation (later Integra LifeSciences), launched CollaDerm, one of the first commercial collagen wound dressings with pre-marketing approval. In 1985, Johnson & Johnson introduced Instat, a collagen sponge indicated for hemostasis.² In 1996, Integra LifeSciences introduced Integra Dermal Regeneration Template (collagen-GAG matrix for burns and complex wounds).³ In 1997 Smith & Nephew released Biostep (collagen-alginate dressing for moist wound healing). In 2000, SouthWest Technologies launched ColActive bovine collagen wound dressing. In 1998 and 2002, Johnson & Johnson received FDA approval for Fibracol (collagen-alginate wound dressing) and Promogran (collagen-oxidized regenerated cellulose matrix for chronic wounds), respectively (originally developed by J&J, now manufactured and sold by Solventum).⁴ These products represent several historical examples showing progressive developments in collagen-based product development. An increasing demand for these products is showing economic impact at the U.S. and global scales. In 2024 U.S. collagen market reached $2.5 billion USD (Global $9.9 billion) and, with compound annual growth rate (CAGR) of 12.9%, is estimated to reach $4.94 billion USD by 2030 (Global CAGR 11.3%, $18.7 billion).¹ Collagen dressings and scaffolds are currently used to manage chronic wounds such as diabetic ulcers, venous stasis ulcers, and pressure ulcers. Useful collagen-based products seem to support wound care by providing a scaffold or matrix for new tissue growth, reducing inflammation, and helping maintain a moist wound environment. This work evaluates the state of scientific evidence on the most common collagen-based products in the market.

Wound care

Wound healing can be defined by four chronological, overlapping phases that include hemostasis, inflammation, proliferation and maturation.^5,6 The hemostasis phase of wound healing consists of platelet hemostatic plug formation and fibrin crosslinking that creates a clot to prevent bleeding.⁷ This response is immediate and can last hours depending on wound size and depth. Once the wound opening has been plugged, initial inflammatory response activates and recruits immune cells, such as neutrophils and macrophages, that in turn, recruit fibroblasts, epithelial and endothelial cells from surrounding tissues through proinflammatory cytokine release.⁸ This initial inflammatory response occurs within hours and may last for days while infection surveillance and removal of bacteria and necrotic tissue is performed. Breached skin barriers allow for the introduction of microorganisms that can begin colonizing the wound surface, without impeding wound healing. However, if bacteria reach critical colonization, wound healing is hindered without triggering acute inflammation. A wound is considered infected when colony counts reach 100,000 organisms per gram of tissue per milliliter of fluid.⁹ Compared with acute wounds, chronic wounds that have been infected are often complicated by a chronic inflammatory response that can disrupt subsequent stages of wound healing and result in impaired wound closure.¹⁰ Overlapping with the resolution of the initial inflammatory phase, the proliferation phase expands and drives the activities of recruited fibroblasts, epithelial and endothelial cells, lasting on a scale of days to weeks.⁵ Fragments from degraded collagen promote infiltrating fibroblast proliferation, deposition of collagen and extracellular matrix (ECM) components during granulation tissue formation. Fibroblast-like cells, originating from wound-macrophages, populate the granulation tissue.¹¹ Immune cells also contribute through the release of growth factors that promote keratinocyte re-epithelialization and endothelial cell angiogenesis programs.¹² The maturation phase of wound healing regulates ECM remodeling, which occurs during new ECM synthesis where fibroblasts, endothelial and epithelial cells release matrix metalloproteases (MMPs) that balance this process with degradation activity.¹³ This balance ultimately defines the barrier functionality and tensile strength of healed skin, which due to differences in glycosylation and organization, can only reach up to 80% of original tissue maximum.¹⁴ Hypertrophic and keloid scars form as this balance shifts toward excessive ECM formation and fibrosis, which continues to undergo remodeling for months or years after wound closure. During the process of wound healing and ECM remodeling, relative abundance of collagen I and collagen III change to support different biological processes. In early wound healing, collagen III is more prevalent to support the inflammatory and proliferative phases. Collagen I, however, becomes more prevalent than collagen III as the wound progresses through ECM remodeling in the late stages of wound healing.¹⁵

Collagen synthesis is a tightly regulated biochemical process that begins with transcription of pro-α1 and pro-α2 chains and translation to pre-pro-polypeptide chains.¹⁶ These chains undergo N-terminal cleavage, lysine and proline hydroxylation, and glycosylation post-translational modifications in the rough endoplasmic reticulum, necessary for the assembly of the procollagen triple helix structure.¹⁷ Processing continues in the Golgi apparatus where procollagen is packaged into vesicles before secretion into extracellular space. Collagen peptidases then cleave the ends of procollagen to produce tropocollagen.¹⁸ Lysyl oxidase facilitates subsequent tropocollagen molecule cross-linking to form collagen fibrils.¹⁹ Molecular oxygen incorporation into nascent collagen is a critical step for collagen escape to extracellular space and proper maturation that provides tensile strength.²⁰ In ascorbate insufficient conditions (e.g., scurvy) collagen molecules do not undergo post-translational hydroxylation by prolyl hydroxylase and lysyl hydroxylase and fail to mature, resulting in weakened vessel formation during angiogenesis and impaired wound healing.^20,21

Wound care is often complicated by factors associated with disease states and comorbidities. For example, diabetes is associated with peripheral arterial disease (PAD), a peripheral vascular disease, that is present in 7–12 million individuals in the United States with a prevalence disproportionately affecting black American patients.²² PAD can result in ischemic peripheral tissues that experience tissue loss, ulcers, and gangrene.²⁰ Venous insufficiency, another peripheral limb ulcer-inducing condition, is a result of inflammatory-induced changes in venous walls and valves that cause retrograde blood flow. Interrupted blood flow in capillaries from hypervolemia or hypertension in veins can cause peripheral edema, deoxygenated venous blood pooling under the skin, venous ischemia and venous hypoxia. Subsequent skin damage in these areas can result in venous leg ulcers (VLUs).²³ These hypoxic conditions are detrimental to wound healing. Hypoxia in wounds can be mild-modest to near-anoxic depending on factors restricting O₂ supply and lead to chronic non-healing or stalled wounds.^24,25 Chronic wounds in the United States continue to be a significant health care burden, affecting upwards of 10.5 million Medicare beneficiaries, and are a major contributing factor to lower extremity amputations.^26,27 Lower extremity amputation mortality rates at 1- and 10-year follow-ups reached staggering rates of 33.7% and 80%, respectively.²⁸

Acute moderate hypoxia, but not severe hypoxia, in wound beds stimulate healing through pro-angiogenic hypoxia inducible factor-1 and vascular endothelial growth factor (VEGF) signaling.²⁰ Severe near-anoxic hypoxia, however, leads to stalled wound healing by downregulating cell signaling and angiogenesis, inhibiting aerobic glycolysis that is required to meet the energy demands of a healing wound as well as by inhibiting collagen synthesis.^20,29,30 Oxygen supply is required for stages of collagen deposition, polymerization, and maturation that are necessary structural components for new capillary tube formation during angiogenesis.^31,32 With poor collagen deposition, weak tensile strength, and immature vessel formation, stalled wound healing exposes the wound bed to greater risk of infection and subsequent complications. Collagen-based dressings can be utilized to improve healing outcomes in ischemic wounds. In recent porcine ischemic full-thickness excisional wound studies, application of a modified collagen gel (MCG) induced monocyte chemoattractant protein-1–1 and VEGF expression, resulting in more endothelial cell infiltration and vascularization during healing.³³ Specifically, the MCG increased the initial transitory inflammation response, proliferative phase, angiogenesis and tissue maturation during remodeling, which showed improvement in three of the four phases of wound healing (inflammation, proliferation, maturation).³⁴ Mechanistically, a MCG dressing improved anti-inflammatory signaling through interleukin (IL)-10 production via the cytokine regulating miR-21-c-Jun N-terminal kinase pathway, increased the ratio of anti-inflammatory/pro-inflammatory macrophage polarization, and promoted angiogenesis through VEGF expression.³⁵ The microRNA miR-200 family has been implicated in hypoxia and ischemic tissue damage.³⁶ In an in vivo diabetic wound healing animal model, topical tissue nanotransfection of anti-miR-200b oligonucleotide promoted therapeutic tissue vascularization with significantly increased collagen deposition at the ischemic wound site.³⁷

Microbes infecting an open wound have the potential to develop a planktonic (free-living) infection, or they may form a polymicrobial aggregate known as biofilm.³⁸ Biofilm aggregates are able to adapt to their environment, as well as evade host immune cells and antimicrobials due to a protective extracellular polymeric layer.³⁹ Treatment of infected wounds is typically a combination of standard of care debridement and topical antimicrobials (such as hypochlorous acid) used in conjunction with systemic antimicrobial therapy. However, the resistant/evasive nature of biofilms coupled with an inability to easily visualize them results in high rates of biofilm recidivism. Biofilm infection not only contributes to open wound chronicity but also undermines the structural integrity of collagen as wound closure occurs. S. aureus biofilm infection, for example, represses miR-143, resulting in an upregulation of collagenolytic matrix metalloproteinase-2 and subsequent degradation of collagen type I as the wound heals. This results in a wound that achieves visual closure; however, the compromised tensile integrity of the newly formed skin means that the wound is likely to recur, seemingly spontaneously over time.⁴⁰ The transepidermal water loss study performed by the NIDDK Diabetic Foot Consortium shows that wounds that close without re-establishing barrier function are likely to recur.^41,42 With 78.2% of chronic wounds showing signs of biofilm infection, identifying or synthesizing wound dressings that not only promote wound healing, but also eradicate biofilms, is a high priority in wound care. The use of biomaterials, including collagen-based dressings and scaffolds, has been beneficial in treating chronic wounds due to their biocompatibility and biodegradability, as well as properties that promote fibroblast infiltration and proliferation.⁴³ Stabilized pericardial collagen matrix, a cross-linked stabilized acellular equine pericardium-derived collagen matrix dressing, has been mechanistically shown to recruit macrophages to wounds and upregulate antimicrobial peptide human keratinocyte β-defensin (HDB-1) during wound healing, as well as calgranulin S100A9. HDB-1 protects the wound from microbial growth by directly disrupting bacterial membranes while S100A9 suppresses bacterial and fungal growth and recruits phagocytic immune cells to the site of injury.⁴⁴

Collagen-based dressings

Collagen serves as the principal structural ECM protein in the skin, tendon, and bone.⁴⁵ The most common collagen types (I–V) are differentially expressed within various tissues throughout the body: collagen I primarily in skin, tendon, bone, muscle, heart, lungs, and vessels; collagen II in cartilage; collagen III in vessels uterus and bowel; collagen IV in basement membranes; and collagen V in hair and nails.^15,46 Because of its biocompatibility, biodegradability, and low immunogenicity, collagen has been used as a biomaterial for a wide range of applications. Collagen has been incorporated into products used for wound dressings, dental surgery, orthopedics, tissue engineering, pharmaceutical therapeutics, as well as food and cosmetic products (Fig. 2).⁴⁷ Traditional dressings composed of inert materials, such as cotton gauze, provide a passive protective barrier to prevent environmental debris and contamination from entering a wound. These dressings provide a layer of protection to promote healing and minimize risk of infection; however, they also have poor absorptive properties and moisture regulation that can cause wounds to dry out or dressings to adhere to wound and result in the need for frequent dressing changes.⁴⁸ Alternatively, semi-permeable wound dressings can adhere tightly to wounds to confine wound exudates and maintain a moist and oxygenated wound healing environment.^48,49 While semi-permeable polyurethane-based dressings permit oxygen, carbon dioxide, and water vapor to pass through, they do not have moisture absorption or MMP neutralizing properties, thus limiting their most effective application to acute wounds and pressure ulcer prevention.⁵⁰ Managing wound exudates, moisture control, MMP neutralizing activity, biocompatibility, low immunogenicity, biodegradability, and antimicrobial activity are desirable properties in wound dressings that have prompted advances in dressing innovation and the development of collagen, alginate, elastin, hyaluronic acid (HA), and chitosan-based bioactive dressings, as well as living skin equivalents.^51–56 Bioactive dressings are often combined with synthetic, chemical, or metallic antimicrobial agents to prevent wound infection during the healing process, which can be essential in the treatment of chronic slow-healing wounds.⁵⁷ Collagen-based bioactive wound care products have been developed for a multitude of applications and come in a variety of forms including dressings, sponges, gels, cross-linked hydrogels, powders, acellular scaffolds, and skin-like substitutes.

Figure 2.

Collagen devices. Collagen, both native and hydrolyzed (image inset), has been used in a multitude of clinical products and devices. These products have shown positive outcomes in patients with regard to wound healing, cardiovascular regeneration, orthopedic repair, dental plugs and regeneration, dietary supplementation, and cosmetic implant and augmentations.

Collagen, as the primary structural protein in extracellular matrices, serves as a base material for wound dressings that are biocompatible, low antigenic, nontoxic, and biodegradable.⁵⁸ Collagen can be sourced from animals, plants or produced as recombinant protein, with porcine collagen being most similar to human collagen. Other animals commonly sourced include bovine, equine, ovine, rodent, poultry, and various marine animals.^59–62 Air-drying or freeze-drying collagen can produce collagen film dressings that easily adhere to wounds and can promote keratinocyte proliferation and epidermal remodeling.⁶³ These films can be combined with growth factors, drugs, or nanoparticles for the slow-release treatment of wounds. However, collagen films are restricted for use on smaller wounds as excessive exudate and leakage can lead to pathogenic infiltration and infection.⁶⁴ Freeze-drying is also used to make collagen sponges that are porous scaffold materials, which retain mechanical strength, plasticity, and absorptive properties.⁶⁵ Collagen sponge properties are arguably more suitable for chronic wounds, dental applications, ulcers, and full-layer burn wounds with high levels of exudate as they are highly absorptive without adhering to wound beds. Native fibrous collagen matrix membranes have been utilized as guided bone regeneration dressings because of claimed better mechanical and osteoinductive properties than collagen sponges.⁶⁶ Collagen membranes combined with growth factors can promote an osteogenic environment that promotes horizontal bone augmentation and regeneration.⁶⁷ With similar activity, collagen plugs have been developed to guide bone regeneration following tooth extractions. Placed in the extraction socket, collagen plugs stabilize blood clots and support an osteogenic environment that can be further promoted with the addition of autologous bone chips.⁶⁶

Crosslinked collagen hydrogels may provide a transparent semi-permeable scaffold with high moisture content to possibly promote wound healing and necrotic tissue autolysis debridement.^68–70 Non-adherence to the wound prevents tissue agitation and damage when the dressing is replaced. Additional crosslinking with HA and chitosan can improve the hydrogel water retention and bacterial barrier function, while also promoting cell migration, proliferation, and adhesion.⁷¹ Collagen hydrogels, like other collagen dressings, can be combined with antibacterial peptides or growth factors to prevent bacterial growth and promote angiogenesis, granulation tissue formation, and tissue regeneration.^72–74

Granulated or powdered hydrolyzed collagen, unlike hydrogels, tends to have minimal crosslinking and can vary in particle size based on methods of preparation (Fig. 3).⁷⁵ Collagen powders can be packed into ulcers, second-degree burns and wounds where they absorb exudate, control minor bleeding, and form a gel-like barrier that protects a moist wound environment.⁵ Collagen powders, similar to hydrogels, can be used as drug delivery systems that are activated upon contact with the wound where high surface area ratio lends rapid delivery for treatments.⁷⁶

Figure 3.

Intact versus hydrolyzed collagen. Intact collagen contains substantial crosslinking necessary for the structural support network it forms in the extracellular matrix. Hydrolyzed collagen peptides (often in granulated or powder products) tend to have minimal crosslinking and can vary in size based on methods of preparation. Receptors on fibroblasts and macrophages can bind hydrolyzed or degraded collagen peptides, which signal for proliferation, infiltration, and immune responses necessary in the wound healing process.

In addition to collagen being used as a bioactive dressing, acellular collagen scaffolds and living skin equivalents are also being utilized as effective skin graft substitutes. Decellularized fish skin, for example, is structurally similar to mammalian skin and exhibits high biocompatibility, porosity, absorptive capacity, biodegradability, and low immunogenicity.⁷⁷ Decellularized marine collagen appears to offer a notable advantage over mammalian-derived collagens by exhibiting a reduced risk of disease transmission when used as a graft in human patients.^78–81 Decellularized collagen grafts from marine or mammalian sources have a structural advantage in the treatment of full thickness wounds and soft tissue augmentation with positive outcomes in thousands of clinical cases dating back to the mid-1990s.⁸² Living skin equivalents are being designed to treat similar severe wounds through tissue engineering. Using a collagen gel, sponge, scaffold, or hydrogel as a common starting material, living skin equivalents are seeded with autologous (patient-derived) or allogenic (neonatal or newborn foreskin-derived) fibroblasts and keratinocytes to create a biocompatible dermal graft equivalent.⁵⁶ These living skin equivalents are applicable to deep wounds where collagen sponges and membranes are insufficient, including diabetic ulcers, venous ulcers, full-thickness burns, and other skin replacement procedures. Decellularized collagen scaffolds are also being used in the development of biological medical devices for hernia and heart valve repair.^83–88

The collagen-based wound care market is evolving rapidly, with several innovative products in the pipeline leveraging advanced biomaterials, bioengineering, and antimicrobial technologies. Rigorous clinical studies are required as new products advance to the market. CollPlant (Israel) is developing rhCollagen (recombinant human collagen) from tobacco plants, expected to enter advanced wound care applications (e.g., 3D-printed skin grafts).⁸⁹ Potential benefits include lower immunogenicity, scalable production, and no animal-derived risks. Yeast/fermentation-derived collagen are under development for the wound care market. Companies such as Geltor (United States)⁹⁰ and Jellatech (Denmark)⁹¹ are working on biosynthetic collagen for medical use, including wound dressings. Phage-integrated collagen comprises bacteriophage-infused dressings designed to target pathogens such as MRSA and Pseudomonas. These dressings are currently in clinical trials by Nextbiotics & Adaptive Phage Therapeutics. In addition, companies such as Pandorum Technologies (India)⁹² are developing 3D-printed collagen-based corneas, while Poietis (France)⁹³ is testing 3D-printed collagen-based living skin for the treatment of burns and chronic ulcers. Drug-eluting collagen dressings are in the pipeline. Platelet-derived growth factor/VEGF-loaded collagen (similar to Regranex but cheaper) are in development by Helix Biomedix.

REGENERATIVE MEDICINE

Regenerative medicine⁹⁴ is a rapidly developing field in health care. This evolving field of study harnesses cells, scaffolds, gene delivery, or their combination to heal damaged or diseased tissue back to their native functional state.⁹⁵ Since the first U.S. FDA approved skin substitute came to market in 1997, tissue engineers have developed multiple approaches to treat a variety of wounds, from mild and severe burns to abrasions and lacerations. While mild wounds may heal in days, severe wounds or wounds with complications from underlying disease or infection require the assistance of a scaffold structure capable of maintaining a moist wound environment, as well as modulating the phases of healing to bring complete closure. Collagen has come to the forefront of many approaches because of its biocompatibility, bioactivity, and low antigenicity.⁵⁸ Often used as a wound dressing, collagen-based products come in sheets, powders, and hydrogels, among others (Tables 1–6).

Table 1.

Level of evidence 1

Dressing	Composition	Level of evidence	Purpose/Claim	Use	Mechanism of action (MoA)	Outcomes study/Trial	References
AlloDerm LifeCell Corporation	Aseptic decellularized human dermal matrix; two forms: freeze-dried or ready to use; contains collagen, elastin, and laminin	Level 1 Level 4 Level 7a	Human skin allograft that has had epidermic and cells removed to prevent tissue rejection	Indicated for soft tissue repair; breast implant reconstruction following mastectomy; skull base reconstruction; periodontal surgeries, dural replacements in neurosurgery, abdominal hernia, head, and neck.	Low levels of fibroblast and blood vessel infiltration compared with other acellular dermal matrices; initial infiltrate of inflammatory macrophages, followed by proliferative phase where endothelial cells can promote revascularization in 7 days (subcutaneous models)	AlloDerm patients showed higher risk of infection and more unplanned operating room visits than other acellular dermal matrices (ADMs)	96–101
Apligraf ■ Organogenesis Inc.	Bovine type I collagen matrix cultured with allogeneic male neonatal fibroblasts and keratinocytes	Level 1 Level 3 Level 5 Level 7b	Full-thickness skin equivalent used to treat chronic diabetic and venous ulcers; temporary biological dressing, providing growth factors to the wound	Indicated for use with standard therapeutic compression for the treatment of noninfected partial and full thickness skin ulcers due to venous insufficiency of >1 month duration and which have not adequately responded to conventional ulcer therapy	Apligraf application invokes an inflammatory response which is essential for acute wound healing; possibly reverts the chronic inflammatory response in nonhealing wounds to a beneficial acute inflammatory signaling response; hypothesized mechanisms include Apligraf secreting growth factors and cytokines of the prohealing pathways, stimulating venous leg ulcer (VLU) cells to activate healing pathways, or a combination of the two	The use of Apligraf in conjunction with compression therapy is a safe and effective way to treat VLUs; patients were twice as likely to achieve complete wound closure by 6 months, and over 60% more effective in achieving wound closure than active control	102–112
Biodesign (BioD) ■ Cook Biotech.	Acellular porcine small intestinal submucosa (SIS); contains ECM collagen, glycosaminoglycans, proteoglycans, and glycoproteins	Level 1 Level 4 Level 5 Level 7a	Creates an environment that allows cells in the body to secrete growth factors and replicate; as the body heals, SIS is gradually remodeled and integrated into the body, leaving behind organized tissue that provides long-term strength	Implantation to reinforce soft tissue; chordee correction; Peyronie’s disease; urethral repair; anorectal fistula repair reinforcement, rectal prolapse/rectal intussusception repair; ventral and hiatal hernia repair; dura mater graft; duraplasty graft; tympanic membrane perforation closure	Reduces profibrotic gene and protein expression (thrombospondin-1 and fibronectin-1) in fibroblasts; reduces levels of latent transforming growth factor which, in combination with fibronectin-1 downregulation, suggests a mechanism with which BioD scaffolds hinder normal and keloid fibroblast profibrotic responses during tissue repair	Laparoscopic paraesophageal hernia repair patients had long and durable relief of symptoms and improvement in quality of life with SIS; SIS myringoplasty yielded reduced surgical time with no adverse events	113–120
Bio-Gide □ Geistlich Pharma AG	Bilayer noncrosslinked porcine collagen membrane with a dense film layer to prevent soft tissue invasion	Level 1 Level 4 Level 5 Level 7a	Collagen membrane for reliable bone regeneration and optimal tissue integration; permits prompt and homogeneous vascularization and so brings about optimal tissue integration and wound stabilization; intended to be used in the treatment of hard and soft tissue defects in oral and maxillofacial surgery	Augmentation around implants placed in immediate or delayed extraction sockets; localized ridge augmentation for later implantation; alveolar ridge reconstruction for prosthetic treatment; filling of bone defects after root resection; cystectomy, removal of retained teeth, guided bone regeneration in dehiscence defects; filling peridontal defects; elevation of the maxillary sinus floor; filling of peri-implant devices; can be used in combination with a void filler, such as Bio-Oss Collagen	Collagen fibers provide an osteophilic matrix that guides bone towards the center of a defect; intrafibrillar mineralization of collagen fibrils occurs spontaneously and presumed independent of osteoblast activity	Long-term data over 12 to 14 years show predictable results of bone augmentations; Bio-Gide use resulted in lower occurrence of wound dehiscence than control; Bio-Oss Collagen and Bio-Gide together limit the loss in alveolar ridge dimensions following tooth extraction	121–132
Bio-Oss Collagen □ Geistlich Pharma AG	90% Bio-Oss natural bone mineral granules and 10% porcine collagen type I	Level 1 Level 4 Level 5 Level 6b	Designed to stabilize clots, promote bone regeneration, and improve bone quality; intended to be used in the treatment of hard tissue defects in oral-maxillofacial surgery.	For augmentation or reconstructive treatment of the alveolar ridge: filling of periodontal defects; filling of defects after root resection, apicoectomy, and cystectomy; filling of extraction sockets to enhance preservation of the alveolar ridge; elevation of the maxillary sinus floor; filling of periodontal defects in conjunction with products intended for guided tissue regeneration (GTR) and guided bone regeneration (GBR); filling of peri-implant defects in conjunction with products intended for GBR	MoA was not directly stated in peer-reviewed literature. Company claims Bio-Oss Collagen promotes rapid vascularization and epithelial regeneration, as well as encouraging bone regeneration.	Prospective 10-year follow-up demonstrated that the great majority of the implants maintained successful soft tissue health and dimensional buccal stability; Bio-Oss Collagen and Bio-Gide together limit the loss in alveolar ridge dimensions following tooth extraction	123,133–141
CellerateRX Surgical Powder □ Sanara MedTech	Hydrolyzed type I bovine collagen	Level 1 Level 2 Level 5 Level 7a	Hydrolyzed collagen fragments do not have to be broken down by the body before use; soluble; compatible with negative pressure wound therapy	Intended for surgical wounds, traumatic wounds, partial and full thickness wounds, and first- and second-degree burns	CellerateRX differentially induced phagocytosis, efferocytosis, and reactive oxygen species (ROS) production in murine wound macrophages at early and late phases of the inflammatory response; potentiated proinflammatory and anti-inflammatory cytokines at appropriate stages of wound healing; improved wound perfusion and closure; improved the quality of wound healing by improving breaking strength of the closed wound tissue; this predicts fewer wound recurrence in CellerateRX-treated wounds	CellerateRX powder appears to attenuate postoperative lymphorrhea and blood loss in patients; suggests benefits for high-risk patients and blood loss complications	142–152
EpiFix □ Mimedx	Dehydrated human amnionic/chorionic membrane (dHACM) tissue graft that contains extracellular biomacromolecules including collagen type IV, V, VII, proteins, fibronectins, laminins, proteoglycans, and GAGs	Level 1 Level 3 Level 5 Level 7b	Processed via a PURION, a patented approach that preserves the ECM and regulatory proteins while removing the contaminants in the blood through a proprietary cleansing procedure	Placental tissue allograft available in sheet and mesh/fenestrated configurations in a variety of sizes to reduce wastage; indicated for acute and chronic wounds, debridement, dehisced wounds, diabetic foot ulcers, venous leg ulcers, pressure ulcers, Mohs repair	Fibroblast and keratinocyte infiltrates are presumed to result in paracrine signaling to support angiogenesis, tissue homeostasis, as well as regulated cytokine and growth factor expression to facilitate wound healing	Subjects treated with EpiFix had a significantly higher probability of complete healing within 12 weeks versus without EpiFix; results confirm the advantage of EpiFix allograft as an adjunct to multilayer compression therapy for the treatment of nonhealing, full-thickness venous leg ulcers	102,153–159
Fibro-Gide® □ Geistlich Parma AG	Type I/III porcine volume stable collagen matrix	Level 1 Level 4 Level 5 Level 7a Level 7b	Intended to be used as an implantable device for regeneration and augmentation of soft tissue in oral and maxillofacial surgery.	For soft-tissue augmentation; localized gingival augmentation to increase KT around teeth and implants; alveolar ridge reconstruction for prosthetic treatment; recession defects for root coverage	Has mechanical properties appropriate to withstand the mechanical stresses that occur after wound closure in soft-tissue augmentation procedures, i.e., it has good volume stability and it withstands early resorption to allow the formation of new soft-tissue and degrades over time; the matrix is designed with an appropriate thickness to provide sufficient space for the ingrowth of new soft-tissue; the device becomes well integrated into the surrounding soft-tissue	Data show soft-tissue thickening around dental implants (1–2 mm gain buccally, 0.68–1.68 mm vertically); the augmented volume is stable in the long run (5-year data); morbidity is lower and surgery time is shorter than with using an autologous graft; used around teeth (single and multiple recessions), Fibro-Gide improves root coverage and gingival thickness	160–169
Hemopatch □ Baxter International Inc.	Synthetic, protein-reactive monomer and a collagen backing	Level 1 Level 3 Level 4 Level 5 Level 6a Level 7a	Absorbable collagen pad intended for wound sealing and hemostasis	Hemostatic device and surgical sealant for procedures in which control of bleeding or leakage of other body fluids or air by conventional surgical techniques is either ineffective or impractical; used to close dural defects following traumatic injury, excision, retraction, or shrinkage of the dura mater	When placed on a wound with blood, or other bodily fluids, the hydroxysuccinimide functionalized polyethylene glycol (PEG) becomes activated and hydrolyzed, resulting in covalent amide bonding/affixing between the patch collagen, PEG, and tissue	Hemopatch is demonstrated to be an effective, easy-to-use hemostatic agent in open and minimally invasive surgery of patients with thrombin- or platelet-induced coagulopathies.	170–182
Mucograft and Mucograft Seal (EU MDR) □ Geistlich Pharma AG	Type I/III porcine collagen matrix	Level 1 Level 3 Level 4 Level 5 Level 7a Level 7b	Faster soft-tissue wound healing compared with autologous grafts; creates predictable soft-tissue dimensions for later soft-tissue management and allows for flexible timing of implant placement; to be used in closed and open healing situations to close wounds of oral mucosa and support wound healing and regeneration processes in case of oral mucosa defects and deficiencies	Covering of implants placed in immediate or delayed extraction sockets; localized gingival augmentation to increase keratinized tissue around teeth and implants; alveolar ridge reconstruction for prosthetic treatment, and recession defects for root coverage	Bilayer collagen structure where mechanism is based on porosity; low-porosity porcine peritoneum-derived layer maintains elastic strength for mucosal suturing; high-porosity porcine skin-derived layer permits tissue adherence, promoting bone-forming cells and tissue growth while also stabilizing blood clot; host tissue infiltrates begin depositing ECM 3 days postimplant; infiltrating macrophages are attributed to degrading the implanted matrix over time	At 6 postoperative months, the computed tomography showed that the bone volume was maintained; it is concluded that Geistlich Mucgraft Seal and Geitlich Bio-Oss are materials that can be used as an excellent possibility of maintenance of the socket structure, postexodontia	82,183–197
OASIS Wound Matrix □ Smith & Nephew	Porcine type I/III collagen; SIS wound matrix dressing	Level 1 Level 5 Level 7b	Support normal physiological functions via facilitating dermal cell infiltration; used in a variety of settings, including long-term, outpatient, and at-home care; naturally derived structure that supports healing process; incorporated and absorbed into the wound.	Management of wounds including partial- and full-thickness wounds, pressure injuries, venous ulcers, chronic vascular ulcers, tunneling and undermining wounds, diabetic ulcers, trauma wounds (abrasions, lacerations, second-degree burns, skin tears), draining wounds, and surgical wounds (donor sites/grafts, post-Mohs surgery, postlaser surgery, podiatric, wound dehiscence).	Contains GAGs that stimulate angiogenesis, inhibit coagulation, organize collagen deposition, promote differentiation and proliferation; matrix absorbs and protects albumin, heparin, fibronectin, FGF-2, and PDGF to promote infiltration of fibroblasts, vascular endothelial cells, neutrophils, and macrophages to the injured area	Wound closure (55%) in comparison with SOC (34%); 7 of 13 wounds closed fully after 12 weeks.	198–204
Omnigraft Dermal Regeneration Matrix/Integra Dermal Regeneration Template (IDRT) ■ Integra LifeSciences	Bovine type I collagen/chondroitin-6-sulfate sponge with thin silicone layer on the epidermal surface	Level 1 Level 2 Level 5 Level 6b Level 7b	Provides an environment for new skin and tissue to regenerate and heal diabetic foot ulcer (DFU) wounds	Postexcisional treatment of life-threatening full-thickness or deep partial-thickness thermal injuries; repair of scar contractures; and treatment of partial and full-thickness neuropathic diabetic foot ulcers that are greater than 6 weeks in duration with no capsule, tendon or bone exposed, when used in conjunction with standard diabetic ulcer care	MoA was not directly stated in peer-reviewed literature. Company claims that this two-layer skin regeneration product offers controlled pore size, porosity, and degradation rate allowing for cellular infiltration, neovascularization, and dermal regeneration while the semi-permeable silicone layer provides epidermal-like protection and moisture control	In RCTs with life-threatening burns, patients treated with IDRT needed thinner skin grafts, causing the donor site to heal sooner; patients with pediatric burns treated with IDRT scored better on multiple physiological markers and had better cosmetic outcomes than patients treated with the standard autograft-allograft technique; patients with DFU showed decreased the time to wound closure, improved components of quality of life, and had less adverse events compared with standard of care	205–212
Promogran Matrix □ Johnson & Johnson	Collagen matrix; 55% bovine collagen and 45% oxidized regenerated cellulose (ORC)	Level 1 level 4 level 5 Level 7b	Oxidized regenerated cellulose and bioactive collagen product that binds to and neutralizes destructive proteases in chronic wound fluid; Reduction of MMP burden in the chronic wound allows endogenous ECM protein cells to proceed to the formation of granulation tissue and normal wound healing	In the presence of exudate, Promogran matrix transforms into a soft, confirmable, biodegradable gel, and thus allows contact with all areas of the wound; the dressing helps create a moist wound bed and an environment that supports wound healing; indicated for non-necrotic chronic wounds without infection including venous and arterial leg ulcers, pressure ulcers, and DFUs	Absorbs wound exudate liquid, forming a biodegradable gel that inhibits MMPs and promotes wound healing; the wound conforming gel binds and protects growth factors in an active state, that are steadily released back into the wound as the collagen matrix is degraded; collagen and oxidized regenerated cellulose bind and inhibit proteases detrimental to the healing process, including MMPs, elastase, and plasmin, likely through steric hinderance	While positive clinical outcomes have been observed, limited evidence exists, and future research is necessary to validate potential clinical and economic benefits	213–222
Therapeutic Nutrition Powder Juven	L-glutamine, L-arginine, citric acid, hydrolyzed beef collagen, sugar, calcium beta-hydroxy-beta-methylbutyrate, ascorbic acid, dl-alpha-tocopheryl acetate, aspartame, zinc sulfate, acesulfame potassium, and vitamin B12.	Level 1 Level 3 Level 5	Ingestible Juven contains a unique blend of key ingredients to help support wound healing	Support wound healing by enhancing collagen production in as little as 2 weeks and to help build and maintain LBM in 4 weeks; also intended as a treatment for sarcopenia patients	MoA was not directly stated in peer-reviewed literature. Company claims collagen proteins give structural support to cells, but they also modulate inflammatory cell function; arginine promotes blood flow and protein production, which can contribute to wound healing; glutamine supports new tissue development and the immune system; vitamins C, E, B12, and zinc support the wound healing process; arginine and HMB improve metabolism and reduce inflammatory response	The specialized amino acid supplement led to a significant increase in collagen deposition (as reflected by hydroxyproline content) in subcutaneously implanted polytetrafluoroethylene tubes; oral consumption reduced cesarean scarring and promoted wound healing; no significant improvement in healing DFU	223–230

Collagen-based products levels of evidence. Level 1 ≥ 3 RCT; Level 2 = 1 well-designed RCT/multi-site study; Level 3 = clinical studies—observational/mechanism of action (MoA); Level 4 = historical cohort (retrospective) or case-control studies (retrospective with control group); Level 5 = other clinical studies (case series or studies as reference treatment, human ex vivo MoA); Level 6a = large animal with MoA; Level 6b = large animal observationnal; Level 7a = small animal with MoA; Level 7b = small animal observational and in vitro. FDA status: □ - cleared; ■ - approved.

Table 6.

Level of evidence 7

Dressing	Composition	Level of evidence	Purpose/Claim	Use	Mechanism of action	Outcomes study/Trial	References
Collagen Gel Thermo Fisher	Tail-derived type I rat collagen	Level 7b	Clear gel providing a 3D matrix or surface coated on tissue culture plates as a substrate for culturing primary cells	Laboratory use: cell culture, co-culture, transwell assay	MoA was not directly stated in peer-reviewed literature. Company claims that rat tail collagen type I can be prepared as a clear gel providing a 3D matrix or surface coated on tissue culture plates as a substrate for culturing primary cells	TGF-β1 treatment of cultured human Tenon’s fibroblasts in collagen gel showed contraction by reduction in collagen gel size	435–437
Puracol Ultra ECM □ Medline	Porcine mesothelium; decellularized, lyophilized, and sterilized porcine peritoneal membrane; contains types I, III, IV collagen; other proteins, including fibronectin, proteoglycans, laminin, elastin, fibroblast growth factors (FGF-b)	Level 7b	Has a significantly higher impact on new blood vessel formation compared with leading ovine collagen ECM and leading collagen/ORC	Completely bioabsorbable dressing is naturally incorporated into the wound over time. High retention of growth factors (FGF-basic, vascular endothelial growth factor [VEGF], and TGF-β1) after the decellularization process, high angiogenetic potential in vitro and MMPs-inhibition to modulate inflammation while promoting healing.	MoA was not directly stated in peer-reviewed literature. Company claims that Puracol Ultra ECM inhibits proteolytic activity and retains collagen networks that highly resemble dermis structures that may contribute to positive wound healing outcomes; high elastin content which can induce cell migration and proliferation; retention and slow release of soluble growth factors (FGF-basic, VEGF, and TGF-β1) promotes angiogenic micro-vessel formation; growth factor retention also promotes host cell adhesion and proliferation; matrix MMP binding suppresses inflammatory state and supports proliferation	Showed comparatively high levels collagen and elastin (vs other grafts and biomaterials), and promoted micro-vessel formation; porcine mesothelium has the potential to be used as a wound healing material, considering its composition, resistance to enzymatic degradation, cytocompatibility, and angiogenic potential; a biofilm model showed that nanozeolite-entrapped antimicrobials have potential for alleviating biofilm-infected wounds	341,418,438

Collagen-based products levels of evidence. Level 7a = small animal with MoA; Level 7b = small animal observational and in vitro. FDA status: □ - cleared; ■ - approved.

Skin substitutes

Natural wound healing re-establishes a barrier between vulnerable inner tissues and an environment full of harmful substances and pathogens. Skin is the body’s first line of defense against environmental factors. Disrupting this barrier through wounds or disease exposes the body to risk of infection, which is exacerbated in individuals with compromising medical conditions such as diabetes and obesity.⁴³⁹ The ability to restore damaged skin with surgical intervention dates back 2,600 years ago. The “father of plastic surgery,” Sushruta, was an innovative surgeon in Kashi, India in the year 600 BCE.⁴⁴⁰ He was renowned for reconstructive surgeries, such as utilizing cheek flaps for nose reconstruction, as well as developing a code of medical ethics. Grafting techniques progressed steadily in the 19th and 20th centuries, leading to a profound breakthrough in 1981 when John Burke and colleagues developed an artificial skin substitute with a top layer of silicone polymer and bottom layer of crosslinked collagen and glycosaminoglycans (GAGs).⁴⁴¹ This provided the foundation for tissue engineering techniques that led to modern collagen-based products designed for biocompatibility, while establishing a structural framework to promote more efficient tissue growth, reduce inflammatory response, maintain a moist environment, and inhibit microbial infection.

The first U.S. FDA approved skin substitutes were TransCyte (Advanced Tissue Science, La Jolla, CA) and Dermagraft (developed by Advanced Tissue Sciences, now marketed by Organogenesis Inc., Canton, MA). These products consisted of a polymer mesh scaffold on which human fibroblasts were cultured which secreted collagen, along with other ECM proteins, growth factors, and cytokines, to support skin wound healing. In the case of TransCyte, the scaffold includes a silicone membrane and the tissue was frozen to kill the cells and allow storage.⁴⁴² Dermagraft was cryopreserved and the cells retained some viability.⁹⁵ As dressings, they are indicated for partial thickness burns, surgical wounds, and diabetic foot ulcers without tendon, muscle, or bone exposure, providing improved patient wound healing outcomes compared with standard of care.^272,442 More recent dressings have drifted away from the necessity of culturing live human fibroblasts, rather, developing dressings comprised of collagen has increased the shelf-life, long-term stability, and shortened preparation time prior to use, while still promoting wound healing outcomes. Combining modern collagen-based biomaterials with growth factors is an approach being used to support tissue regeneration in chronic wounds. For example, VEGF fused with a collagen-binding domain has been incorporated into a collagen-based biomaterial to essentially create a slow-release drug delivery system that promotes angiogenesis and revascularization of chronic diabetic wounds.⁴⁴³ Similar methods have been developed for collagen-B-cell leukemia/lymphoma 2-adipose-derived stem cell scaffolds,⁴⁴⁴ collagen-copper/cobalt bioactive microfibrous glass mats,⁴⁴⁵ and collagen matrix hydrogel delivery of basic fibroblast growth factor (bFGF).⁴⁴⁶ Puracol Ultra ECM has also been used to deliver FGF to promote regenerative wound healing in a small animal aortic ring assay.⁴⁴⁷

Cardiovascular collagen

Defects in collagen from mutations in the collagen type I/III genes can be responsible for cardiovascular diseases and abnormalities such as aortic dilation, aortic aneurysms, arterial dissection, and rupture.⁴⁴⁸ While defects in collagen can result in cardiovascular abnormalities, tissue engineered collagen products can be used to treat them in vivo. The most common surgical treatments for atherosclerosis, for example, still include vascular bypass and replacement. Patents with atherosclerosis, however, often have poor vein and artery health, making them poor candidates for autograft harvesting. Collagen-based vascular grafts have become alternative materials for transplantation when combined with other natural (fibrin, elastin) or synthetic (polyurethane, polydioxanone, polycaprolactone) materials, which can bolster collagen’s mechanical properties without diminishing the beneficial biocompatibility, cell adhesion, biodegradability, hydrophilicity, and weak immunogenicity properties of collagen.⁴⁴⁹ Dacron vascular grafts, for example, when coated with collagen have long-term secondary corrected 8-year patency rates >90%.⁴⁵⁰ Collagen engineered vascular products can also be utilized as drug delivery systems with VEGF and bFGF, promoting post-transplant endothelialization while limiting thrombosis and intimal hyperplasia.⁴⁵¹ In the case of bFGF delivery, heparinized collagen-coated vascular grafts (with embedded heparin) resulted in long term patency by mimicking the mechanism of heparin sulfate present in native ECM of endothelial cells that binds and stabilizes bFGF, releasing it upon vascular wall damage, resulting in localized bFGF release and proliferation of endothelial cells.⁴⁵¹ Antibiotics and antimicrobial peptides have also been incorporated into collagen-based vascular grafts to prevent perioperative infection.⁴⁵² Collagen-based hydrogels have also been used as an injectable therapeutic to prevent myocardial infarction by providing ventricular wall thickness and mechanical support without hindering myocardial contraction. Studies have shown, however, that there is a therapeutic window post-myocardial infarction when this treatment is most beneficial because of pathophysiological stages of necrosis, inflammation, proliferation, and maturation.^453,454 These collagen hydrogels have also been used as delivery systems for therapeutic drugs and stem cells to treat cardiovascular disease.⁴⁴⁹ Akin to hydrogels, collagen-based patch scaffolds have been developed to serve as epicardial dressings for reconstruction of large cardiovascular defects. These dressings can be loaded with conductive material, bioactive drugs, stem cells, and exosomes to facilitate the reconstruction and regeneration of large cardiac and vascular defects.⁴⁴⁹

SKIN HEALTH

Skin collagen synthesis

Skin, the body’s largest organ, structurally serves as a protective barrier against environmental stressors and damage. The importance of maintaining skin health throughout one’s lifetime has become a more widely accepted practice as awareness has spread of skin cancer as being the most diagnosed cancer in the world that is also preventable.⁴⁵⁵ Evidence for age-related weakened barrier functions has also supported the need for healthy skin practices.⁴⁵⁶ Photoaging, caused by prolonged exposure to extrinsic ultraviolet (UV) radiation, has not only been identified as one of the main risk factors for melanoma, but also has a profoundly detrimental effect on ECM deposition in the dermis.⁴⁵⁷ Photoaging causes fragmentation and degradation of collagen, the main structural component of ECM.^458,459 Disruptions in collagen synthesis have been correlated with a spectrum of diseases that have been traced back to over 1,000 mutations in patients.⁴⁶⁰ Heritable genetic disorders have been identified that cause disrupted collagen fibril formation in skin biopsies.⁴⁶¹ Ehlers-Danlos Syndrome, for example, is one such disorder mostly attributed to mutations in COL5A1 and COL5A2 genes, and in rare cases COL3A1. Resulting haploinsufficiency of type V collagen can manifest symptoms in varying degrees of severity from mild to fatal, including skin hyperextensibility, joint hypermobility, tissue fragility, delayed wound healing and atrophic scarring, and vascular ruptures.^462–467

Skin collagen is primarily derived from triple helix procollagen produced by fibroblasts.¹⁵ Collagen turnover occurs at different rates in different tissues, with a half-life of skin collagen (insoluble) of approximately 15 years, whereas cartilage collagen half-life can reach 117 years.⁴⁶⁸ Endogenous synthesis of skin collagen studies in 1964 revealed glycine as the most abundant amino acid making up its triple helical structure.^469,470 Further study has shown that collagen’s amino acid composition is roughly 1/3 glycine, 0.7/3 proline (+hydroxyproline), and 1.3/3 other amino acids, and that limiting glycine and proline limits maximal collagen synthesis,⁴⁷¹ with proline biosynthesis as a rate limiting factor.⁴⁷² Glycine, proline, and hydroxyproline have now made their way into global markets in the form of hydrolyzed collagen peptides present in wound dressings, as well as skin care and food products.

Topical collagen applications

Topically applied collagen products are becoming more popular in skin care markets. However, topical applications of intact collagen capable of replacing endogenous collagen within the skin is a common misconception. Native collagen that has been topically applied has poor permeability and cannot penetrate the skin barrier.⁴⁷³ When hydrolyzed, even collagen peptides larger than six to seven amino acids cannot be efficiently absorbed (Fig. 3).⁴⁷⁴ One of the most common used topical collagen products is hydrolyzed collagen tripeptide (CTP) sequence Gly-X-Y (often Gly-prolyl-hydroxyproline [Pro-Hyp]). It is an abundantly available biological material that has low allogeneic properties, making it a desirable component for topical and oral collagen-based products.⁴⁷⁵ The application of CTP has been considered to contribute to smoothing of facial wrinkles and improving skin elasticity; however, these observations are also coupled with increased moisture content. Collagen is hygroscopic (attracts water), so when applied topically, it forms a moisturizing film that plumps the skin, reducing fine lines temporarily. It may also temporarily strengthen the skin barrier, preventing moisture loss (e.g., in dry or aged skin). High-molecular-weight collagen (in creams/sheets) may sit on the skin’s surface, creating an optical smoothing effect—similar to silicone scar sheets.⁴⁷⁶ Some hydrolyzed collagen peptides (small fragments) can arguably signal fibroblasts (skin cells) to boost collagen and elastin synthesis (via transforming growth factor-β [TGF-β] and other growth factors).⁴⁷⁶ Some collagen products may have antioxidant properties that neutralize free radicals (reducing UV-induced damage).⁴⁷⁴ Most of these plausible mechanisms require rigorous testing in appropriately designed clinical trials. The hype for such cosmetic and aesthetic products in the market seems to be frequently generated by aggressive marketing strategies not supported by rigorous science. Appropriate consumer caution and due diligence are thus warranted.

Collagen-based fillers

Collagen injections have been a trend in cosmetic research to fill facial voids, enhance volume and remove wrinkles. Conceptually, collagen injections in the mid-to-deep layers of the skin act as support structures that remove wrinkles and skin folds. Products claim that injected collagen is absorbed within a month of injection and replaced by native de novo synthesized collagen by 3 months postinjection.^477,478 Rigorous clinical studies are necessary to support these claims. Recent retrospective analysis of clinical data for facial wrinkles treated with collagen type III injections showed significant improvement in experimental subjects compared to control subjects at 30 days postinjection.⁴⁷⁹ Ninety days postinjection, however, there was no significant difference between the groups, suggesting that the collagen filler was broken down and resorbed rather than replaced.⁴⁷⁹ Individuals considering use of collagen dermal fillers should also be cautioned that mild to severe complication risks have been associated with their use, including discoloration, necrosis, infection, vision loss, granuloma formation, foreign body reaction, and biofilm formation.^480,481 Because of potential adverse events, including autoimmune response, which required sensitivity reaction testing, several collagen fillers (including Zyderm, Zyplast, Cosmoderm, Cosmoplast) have been discontinued.^399,400 Noncollagen dermal fillers have also been developed as potentially safer or longer lasting alternatives. Injectable poly-L-lactic acid (PLLA), HA, calcium hydroxyapatite (CaHA), polymethyl methacrylate (PMMA), polyalkylimide, and silicone implants have been used to varying degrees of success.^263,482 Challenges and complications vary depending on biodegradable (PLLA, HA, CaHA) and nonbiodegradable (PMMA, polyalkylimide, silicone) properties.⁴⁸³ Because of the short-term effects of collagen fillers that are typically depleted 3–4 months postinjection, HA has become a more commonly used alternative which can last 12–24 months.⁴⁸⁴ Collagen and HA dermal fillers currently have in vivo mechanisms of action that are not fully understood, as well as short and long-term complication risks that should be discussed with physicians before injection procedures. Additional rigorous scientific studies are required.

ORTHOPEDICS AND DENTAL APPLICATIONS

Tendon repair

Collagen-based scaffolds and matrices are used in bone grafts, cartilage repair, and tendon or ligament reconstruction (Fig. 2). They serve as a scaffold that promotes the regeneration of bone and soft tissues in joint repairs and spinal surgeries. Sports injuries, for example, are often associated with bone and tendon injury as a result of overuse or trauma. Tendons are connective tissues with a multitude of organized collagen fiber bundles.⁴⁸⁵ Tendon injuries are painful and typically slow to heal, even when treated with nonsurgical drug, stem cell, or physical therapies.⁴⁸⁶ bFGF can aid in accelerated tendon healing by promoting neovascularization during the proinflammatory phase, while also stimulating fibroblast production of type III/I collagens during the cell proliferation phase of healing. Overuse of bFGF can overstimulate these processes however, leading to fibrotic scar formation and potential tendon adhesions.⁴⁸⁷ A common musculoskeletal disability that occurs in approximately 8% of adults is rotator cuff damage, resulting from acute tear injuries or age-related degeneration.⁴⁸⁸ The use of acellular scaffolding, such as GraftJacket, retains intact collagen ECM and blood vessel channels with low immunogenicity.^296,297 These acellular dermal matrices show promising results in repairing large rotator cuff tears in patients, with little to no adverse events.²⁹⁷ Another application of collagen-based products to support orthopedic regeneration comes from the use of dehydrated human placental allograft amnion-chorion membrane material (NuShield) that retains collagens, ECM proteins, growth factors, elastin, glycoproteins, and proteoglycans.³⁰⁵ When applied to tendon, spinal or nerve damage, placental allografts release growth factors and cytokines to promote fibroblast and keratinocyte migration and proliferation, while paracrine signaling subsequently regulates localized inflammatory responses.³⁰⁵ This dehydrated placental allograft material has shown promising results as regenerative treatments for tendons, nerves, spinal adhesions, and fibrosis, as well as treatment for chronic wounds.^489,490

Bone grafting

Bone repair is a major challenge in the musculoskeletal regenerative therapy field. Common bone defects are the result of osteoporosis weakening of bones, traumatic fractures and breaks, osteomyelitis, periodontitis, congenital defects, and hereditary diseases.⁴⁹¹ Mutations in the COL1A1 and COL1A2 genes can result in multiple subtypes of osteogenesis imperfecta or “brittle bone disease.”⁴⁶⁷ The lack of suitable donors for bone grafting is compounded by the risk of immune rejection, while autologous bone grafting is limited by the patient’s own available donor material, which also carries the risk of causing irreversible damage when harvested. The application of collagen-based biomaterials provides a matrix for cell infiltration and proliferation that, when combined with porous material and factors such as connective tissue growth factor (CTGF) or bone morphogenic proteins (BMP), establish an osteogenic microenvironment that promotes osteoblast deposition of bone matrix.^492,493 Recent clinical trials have shown that the use of calcium phosphate cement is useful in reducing fractures and pain while improving functional outcomes.⁴⁹⁴ However, limited osteoinductivity and resulting tensile strength make it an undesirable void filler for larger defects.⁴⁹⁴ Biomaterials have been making significant progress as alternative bone void filler options that contain collagen to promote bone healing processes. A combination of calcium phosphate, dibasic (DICAL), and purified type 1 bovine collagen (CopiOs) has been used as an osteoconductive sponge scaffold to promote regeneration of bone voids (Table 3). The DICAL-collagen product, when coated with BMP, has shown success in filling post-harvest iliac crest donor sites in spinal fusion surgery and in promoting bone growth in large tibial defects in animal models by creating a microenvironment that supports osteogenesis.³⁴⁶ This approach is designed to mitigate donor site risk complications of morbidity (9.4 – 49%) and chronic pain at iliac crest autograft harvest sites.^495–499 Combining collagen-based biomaterial (Healos) with bone marrow aspirate (BMA), that has undergone selective cell retention of mesenchymal stem cells (MSCs), has produced a substitute for autologous iliac crest bone grafts in lumbar spinal fusion procedures.³⁸² Strips of this biomaterial loaded with MSCs and CTGF have been implanted in posterolateral fusion procedures in 21 patients, 100% of which achieved successful solid bilateral fusions.³⁸² For the treatment of long bone fractures, porous beads comprised of hydroxyapatite, tricalcium phosphate ceramic, and fibrillar type 1 bovine collagen (CollaGraft) have been developed to create a biodegradable osteoconductive scaffold.²⁵³ When preloaded with BMA, this biodegradable scaffold has been used successfully to promote bone repair in patients with long bone fractures.^253,254 This combination has also shown promise as an autologous bone graft substitute in large animal models.²⁵⁵ The use of collagen-based biomaterials for treatment of bone damage has proven to be beneficial in repairing small bony voids and long bone fractures, as well as providing scaffold and osteogenic support for bone fusion procedures (Tables 1–6). These same principles have been used to promote wound healing and bone regeneration in oral and maxillofacial surgeries.

Table 3.

Level of evidence 3

Dressing	Composition	Level of evidence	Purpose/Claim	Use	Mechanism of action	Outcomes study/Trial	References
ACell MatriStem Matrix □ Integra LifeSciences	Acellularized basement membrane and tunica propria layers of the porcine bladder; ECM proteins that include type I/III collagen, glycosaminoglycans, growth factors	Level 3 Level 4 Level 6a	Wound management solution for irregular, tunneled, or undermined wounds; applied as either a powder or paste; the particulate solution provides intimate contact with all areas of the wound bed	Treat esophagojejunal anastomotic leaks; vesicovaginal fistula; deep partial thickness burns and wounds; esophageal stenosis; seal surgical sites and prevent leakage.	Induces a host-derived tissue remodeling response; stimulates neovascularization through a number of growth factors and functional proteins such as collagen, laminin, and elastin; inflammatory reactions are uncommon, given the acellular, inert nature of urinary bladder matrix	Use in deep partial-thickness burns enabled healing by 29 days on average without requiring autografts; 75% of cases of vesicovaginal fistula treated with MatriStem had no fistula drainage and progressed to full healing; an alternative for the treatment of esophageal stenosis is presented, which uses a biological scaffold and an innovative surgical procedure where all patients had a favorable clinical outcome with immediate recovery from the procedure and reinstated oral intake after 7 days	335–340
CollaPlug ■ Zimmer Biomet	Type I/III bovine collagen absorbable non-friable sponge	Level 3 Level 5 Level 7b	Material to help promote clotting	Control bleeding and stabilize blood clots as well as protect the wound bed while accelerating the healing process.	MoA was not directly stated in peer-reviewed literature. Company claims that CollaPlug enhances clot formation and accelerates formation of granulation tissue while it absorbs up to 60 times dressing weight in fluids.	Effective local hemostatic material following minor oral surgery in patients under oral anticoagulant therapy; also shows acceleration of soft tissue healing and reduce postoperative pain	341–345
CopiOs Bone Void Filler □ ZimVie	Calcium phosphate, dibasic (DICAL) and purified type 1 bovine collagen	Level 3 Level 6b Level 7a Level 7b	Synthetic bone graft material consisting of mineralized, lyophilized collagen that has been formed into sponges of various sizes for surgical implantation.	Used for bone grafting and rigid fixation techniques for stabilizing bone voids	During the remodeling process CopiOs Bone Void Filler act as a scaffold that provides a moderately acidic environment that promotes solubility of osteoinductive growth factors for new bone formation. CopiOs promotes aerobic glycolysis and proliferation in cells seeded within its collagen matrix. Seeded cells have fast calcium release and high levels of p38 and ERK phosphorylation, suggesting that CopiOs promotes activation of these pathways.	Patients undergoing spinal fusion with CopiOs bone void filler was used showed a decrease in the volume of bony void at 3- and 6-month follow ups, with no pain reported.	346–349
Cutimed Epiona □ Essity	90% native bovine collagen, 10% calcium-sodium alginate	Level 3 Level 4 Level 5	Mimics the function of a healthy dermis and boosts the wound healing process; eliminates harmful factors by binding MMPs; enhanced granulation by promoting cell growth	Easy to combine with your current therapies (e.g., compression therapy); broad indication for treatment of all wounds healing by secondary intention, free of necrotic tissue; can be folded or rolled up depending on wound type (deep wounds); indicated for diabetic foot ulcers, donor sites, pressure injuries, surgical wounds, trauma wounds, venous leg ulcers	MoA was not directly stated in peer-reviewed literature. Company claims that contact with wound exudate rehydrates Cutimed Epiona to a gelatinous form that keeps wound environment moist; binds and inhibits MMPs and reduces inflammation	Patients exhibited a decrease and wound exudate and wound area after 3 weeks of treatment with no infection or adverse events reported	350–353
INSPIRIS RESILIA ■ Edwards Lifesciences	Aortic valve, treated bovine pericardium	Level 3 Level 4 Level 5	Improves heart valve replacement safety and efficacy; significant improvement in calcium-blocking properties	Indicated for aortic valve replacement	MoA was not directly stated in peer-reviewed literature. Company claims that stable-capping permanently blocks free aldehydes to prevent calcium binding within the tissue	Patients showed a reduction of transvalvular pressure gradients and lower trans-prosthetic pressure gradients	354–358
Integra Bilayer Matrix Wound Dressing (IBWMD) □ Integra LifeSciences	Bovine type I collagen/chondroitin-6-sulfate sponge with thin silicone layer on the epidermal surface	Level 3 Level 4 Level 5	Controlled pore size, porosity and degradation rate of the sponge enables cells to infiltrate, proliferate, and aid in the healing process; the semi-permeable silicone layer provides epidermal-like protection and moisture control	Support the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, surgical wounds, trauma wounds, and draining wounds; not indicated for third degree burns	Facilitates neodermal reconstruction with regenerative rather than inflammatory healing; fibroblasts infiltrate by day 7, myofibroblasts infiltrate by week 3 and deposit collagen, by week 4 native collagen replaces Integra collagen and becomes fully vascularized; following vascularization, silicone cover is removed; can provide antibiotic delivery	IBWM demonstrated progressive DFU wound healing, with 95% mean wound reduction at 12 week; complete wound closure was achieved by 70% of patients after 12 weeks; no recurrences were observed at follow-up	359–364
Integra Wound Matrix □ Integra LifeSciences	Bovine type I collagen/chondroitin-6-sulfate sponge	Level 3 Level 4	Controlled pore size, porosity, and degradation rate enables cells to infiltrate, proliferate, and aid in the healing process	Support the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds; not indicated for third degree burns	MoA was not directly stated in peer-reviewed literature. Company claims IWM is an effective method to treat deep skin defects in elderly multimorbid patients with deep facial wounds by promoting dermal regeneration	IWM resulted in favorable take rates, functional and early cosmetic outcomes in deep facial wounds; all but one graft had complete take without any complication, whereas one graft had partial graft loss (30%); all defects showed significant shrinkage of 61%	365–369
KollaGen II Simple Supplements	Avian sternal collagen type II hydrolysate	Level 3	Nutritional supplement to reduce symptoms of joint damage	A dietary supplement that may be beneficial for patients suffering from degenerative joint diseases, including cartilage injuries, connective tissue disorders, polychondritis, joint defects, osteoarthritis, and rheumatoid arthritis	Some orally administered collagen type II hydrolysate-derived peptides are absorbed by the intestine and are circulated in the blood stream to eventually reach cartilage tissue and, possibly, activate collagen biosynthesis in chondrocytes to alleviate joint pain	Administration of 2,000 mg/day of collagen type II hydrolysate for 60 days improved essential symptoms in individuals suffering from joint diseases, including the range of motion, general pain, and muscle strength	370
SkinTemp II □ Human BioSciences	Collagen sheets; 100% nonhydrolyzed type 1 bovine native collagen	Level 3 Level 5 Level 7b	Kollagen technology process protects and retains significantly more native triple helical protein structure, thus allowing superior stability of the molecule and scaffolding through all four phases of wound healing	Management of burns, scrapes, blisters, sores, ulcers, acute and chronic wounds, superficial, partial- and full-thickness wounds, infected and noninfected wounds, and minimal to heavily exudating wounds	Triple helical structure is more stable, having high tensile modulus in wound environment, providing scaffold to chemotactically attract and guide fibroblast migration for collagen deposition and improved wound healing	Type I bovine collagen matrix provided a safe, readily available alternative to traditional methods of second intention healing; it minimized wound care while reducing the time for complete healing	371–374

Collagen-based products levels of evidence. Level 3 = clinical studies—observational/mechanism of action (MoA); Level 4 = historical cohort (retrospective) or case-control studies (retrospective with control group); Level 5 = other clinical studies (case series or studies as reference treatment, human ex vivo MoA); Level 6a = large animal with MoA; Level 6b = large animal observational; Level 7a = small animal with MoA; Level 7b = small animal observational and in vitro. FDA status: □ - cleared; ■ - approved.

Dental applications

Collagen membranes and graft materials are used in oral surgery, particularly for periodontal regeneration and guided bone regeneration (Fig. 2). Periodontal disease, or gum disease, commonly refers to inflammatory disorders ranging from mild reversible gingivitis to the more severe irreversible periodontitis gum infection that causes loss of connective tissue and bone support, often leading to tooth loss.⁵⁰⁰ Beyond causes such as plaque buildup, periodontal disease has been defined as a systemic disease associated with a host of other morbidities.⁵⁰¹ Severe periodontitis reached a prevalence of 23.6% in dentate adults in 2020, which is striking when considering that periodontitis is the medical basis for roughly 25–38% of tooth extractions.⁵⁰² To promote better healing and recovery following dental surgery procedures, researchers have been developing collagen-based materials that promote clotting, tissue regeneration, and bone preservation. The use of bioabsorbable collagen membranes in periodontal regeneration procedures also prevents the need for membrane removal surgery while also limiting the risks of bacterial colonization.⁵⁰³

An absorbable porous collagen sponge material (CollaCote) is beneficial as a collagen-based product that can be packed into a root canal space following debridement, along with a barrier of mineral trioxide aggregates (Table 2). This collagen matrix is fully absorbed in 10–12 days and promotes obturation, or closure, of the canal space through host cell migration and osteoinductivity into homogeneously spaced micropores.^246,247 After tooth extraction, applying a biodegradable collagen plug (CollaPlug) before socket suturing has been shown to reduce postoperative bleeding and pain. The plug acts as a hemostatic material by absorbing fluids, enhancing clot formation, and accelerating granulation tissue development.³⁴¹ The same collagen plug has demonstrated, with the addition of platelet rich fibrin, that it contributes to alveolar ridge preservation in extraction sockets, preserving bone width for up to 4 months.³⁴² Animal studies have shown that fibrillar collagen (CollaTape) promotes early phases of bone healing through osteoblast surface fibronectin-mediated adhesion and collagen-driven angiogenesis.²⁴⁸ This effect was limited by the degradation of collagen dressing within 5 weeks of application. Longer-term ridge preservation could be achieved by adding synthetic bone particles to the extraction socket prior to closing the wound with collagen dressing.

Table 2.

Level of evidence 2

Dressing	Composition	Level of evidence	Purpose/Claim	Use	Mechanism of action	Outcomes study/Trial	References
ArteGraft ■ LeMaitre Vascular	Acellular collagen vascular graft of bovine origin	Level 2 Level 3 Level 4 Level 5 Level 6a	Long-term durability and secondary patency rates; easy surgical handling and suturability; strong collagen matrix that retains the original artery cross weave	Intended for use distal to the aorta as a segmental arterial replacement, as an arterial bypass, as an arteriovenous shunt where more conventional methods have proven inadequate, or as an arterial patch graft	ArteGraft is simply to serve as a substitute conduit for blood where bypass or replacement of occluded/diseased arterial segments is required, or to establish a conduit for hemodialysis	Conformity to the applicable requirements and confirmed that the subject device is safe and performs as intended and claimed; is a state-of-the-art device for use for vascular access or in vascular bypass or repair; limb salvage rate at one year was 83.6% and at five years was 86.2% for patients with critical limb ischemia	231–236
Collagen meniscus implant (CMI) ■ Stryker	99% tendon-derived type I bovine collagen; small quantities of GAGs: chondroitin sulfate, sodium hyaluronate	Level 2 Level 5 Level 7b	CMI implant reinforces soft tissue and provides a resorbable scaffold that is replaced by the patient’s own soft tissue; is not a prosthetic device and is not intended to replace normal body structure	Designed to function as an absorbable template to facilitate host meniscus tissue regeneration in patients who have an irreparable meniscus tear or loss of meniscus tissue, ACL reconstruction, knee realignment, chondral resurfacing	The CMI meniscus tissue implant is slowly absorbed and replaced by patient’s native collagen tissue; can be preseeded with mesenchymal stem cells (MSCs) or meniscus cells before implantation	One year after implantation, hybrid fibrous and meniscus-like fibrochondrocytic matrix have been identified within the collagen implant suggesting its potential to integrate with host tissue; at that time, remnants of the CMI may be present in 10% to 25% of cases; improves short-term outcomes, but tissue deposition is limited and (partial) resorption occurs in several years	237–240
ColActive Plus an Colactive Plus AG Hartmann USA	Collagen, sodium alginate, EDTA carboxymethyl cellulose, silver chloride	Level 2 Level 5 Level 7b	Dressing maintains a moist wound environment at the wound surface that aids in the formation of granulation tissue and epithelialization; silver chloride provides an effective broad spectrum of antimicrobial activity; helps remove zinc to inhibit matrixins	Management of full- and partial-thickness wounds including: pressure injuries, diabetic ulcers, ulcers caused by mixed vascular etiologies, venous ulcers, donor and graft sites, abrasions, traumatic wounds healing by secondary intention, dehisced surgical wounds, first-, and second-degree burns	Gelatin sheet that directly contacts with wound and exudates; the dressing maintains a moist wound environment at the wound surface that aids in the formation of granulation tissue and epithelialization; EDTA inhibits MMPs; carboxymethyl cellulose and alginate maintain moist wound environment and activate silver ion; antimicrobial silver chloride disrupts bacterial metabolic cycle	The use of Colactive silver dressing has less pain, less itching in the donor area, and a shorter average recovery time than Vaseline gauze	221,241–245
CollaCote ■ Zimmer Biomet	Porous, nonfriable collagen sponge; type1 bovine collagen	Level 2 Level 5 Level 7a level 7b	Aids in wound closure and controls bleeding in palatal donor sites, mucosal flaps; provides matrix for tissue ingrowth	Intended for surgical wounds, periodontal surgical wounds, extraction sites, dental sores, oral ulcers (noninfected or viral), suture sites, burns, traumatic wounds; being used to treat bone defects associated with endodontic treatment complications	Host cell migration from surrounding tissue, osteoinductivity, mediated by collagen structure and homogeneously distributed micropores; absorbs and regulates bleeding and blood clots while also protecting the wound site and promoting healing	CollaCote significantly accelerated palatal wound healing and reduce the patient’s pain and discomfort	246–251,252
CollaGraft ■ Zimmer Biomet	Porous beads; 60% hydroxyapatite and 40% tricalcium phosphate ceramic, fibrillar type I bovine collagen	Level 2 Level 4 Level 6b Level 7a	Bridges segmental long bone defects	Treatment of acute long bone fractures and traumatic osseous defects with bone marrow and rigid fixation; can impregnated with antibiotics	Hydroxyapatite provides a slightly resorbable scaffold to facilitate new bone ingrowth and calcification; tricalcium phosphate is a resorbable component that binds bone material; these components together provide a biodegradable osteoconductive scaffold that promotes new bone ingrowth and remodeling while preserving mechanical strength; can be used with autogenous bone marrow for treating long fractures	Showed the same efficacy as autogenous iliac graft in the treatment of acute long bone fractures over 6–12 months; CollaGraft with bone marrow: at 21 days, new woven bone and osteoblasts were seen in contact with both the collagen and hydroxyapatite/β-tricalcium phosphate components; newly formed bone ossicles were observed in association with the collagen component	253–259
CosmoDerm □ Abbvie	Human-based collagen	Level 2 Level 4 Level 5	Replenish skin’s lost collagen	Injected into the superficial papillary dermis for correction of soft tissue contour deficiencies, such as wrinkles and acne scars	MoA was not directly stated in peer-reviewed literature. Company claims it is an injectable dermal filler formulated for fine line wrinkles and facial contour defects.	Resulting nonsevere adverse event rate of 33.3% for CosmoDerm (1/3 injections)	260–262
CosmoPlast □ Abbvie	Human-based collagen crosslinked with glutaraldehyde	Level 2 Level 5 Level 6b	Improves facial appearance by smoothing wrinkles and folds	Injected into the mid to deep dermis for correction of soft tissue contour deficiencies, such as wrinkles and acne scars.	MoA was not directly stated in peer-reviewed literature. Company claims it is an injectable dermal filler formulated for fine line wrinkles and facial contour defects.	Treatment of mid to deep dermal defects lasts for 4–7 months)	263–267
DermACell ■ LifeNet Health	Acellular human-derived dermal matrix that is decellularized, removing donor DNA, and retains native growth factors, collagen, and elastin	Level 2 Level 4 Level 5 Level 7a	Matracell removes a minimum of 97% of donor DNA, allowing for rapid cellular infiltration and re-vascularization in wound healing	Treatment of chronic nonhealing wounds such as diabetic foot ulcers	Matracell removal of donor DNA allows for rapid cellular infiltration and revascularization; CD31 positive cell infiltration and vessel formation by day 7; high levels of fibroblast and blood vessel infiltration suggest DermACELL tissue incorporates into the host tissue	Significantly higher percentage of completely healed ulcers by the 16-week follow-up compared to the conventional care group	98–100,268–271
Dermagraft ■ Organogenesis	Three-dimensional polymer scaffold containing metabolically active human fibroblasts that secrete collagen, other ECM proteins, growth factors, and cytokines	Level 2 Level 3 Level 7a Level 7b	Diabetic foot ulcer treatment composed of fibroblasts, extracellular matrix, and a bioabsorbable scaffold.	Treatment of full-thickness diabetic foot ulcers greater than six weeks duration which extend through the dermis, but without tendon, muscle, joint capsule, or bone exposure. Indications beyond DFUs, include the treatment of dystrophic epidermolysis bullosa, chronic surgical wounds, and wound dehiscence after amputations.	During manufacturing, human fibroblasts proliferate to fill the interstices of this polyglactin mesh scaffold and secrete collagen, other ECM proteins, growth factors, and cytokines; remains metabolically active following wound bed implantation	At 12 weeks after initiation of therapy, Dermagraft treatment led to a 64% increase in the proportion of patients exhibiting complete wound closure when compared with patients receiving conventional therapy	272–278
Evolence ■ Johnson and Johnson	Collagen filler; 3.5% type 1 fibrillar porcine collagen crosslinked with d-ribose	Level 2 Level 5 Level 7a	Reduces wrinkles and facial folds; less immunogenic than bovine collagen	Injectable product indicated for the correction of moderate to deep facial wrinkles and folds such as nasolabial folds	Glymatrix crosslinking technology improves clinical persistence by providing resistance to collagenolytic degradation; fibroblast infiltrates colonize the matrix and secrete new collagen; areas of new collagen deposition become vascularized and, after 12–24 months, become integrated in the dermis	6 months post-OCR visit, 91.2% of subjects continued to rate the nasolabial fold treated with Evolence as “better” or “much better” than pretreatment; no hypersensitivity reported; maintained durability for 18 months on average	279–282
Fibracol Plus □ Johnson & Johnson	Collagen wound dressing with alginate; 90% collagen, 10% calcium alginate	Level 2 Level 5 Level 7a Level 7b	Structural support of collagen with the exudate management of alginate; absorbent alginate composition helps maintain a moist wound environment conducive to granulation tissue formation and epithelialization	Management of exuding wounds including: full- and partial-thickness wounds; pressure injuries; venous ulcers; ulcers caused by mixed vascular etiologies; diabetic ulcers; donor sites and other bleeding surface wounds; traumatic wounds healing by secondary intention; dehisced surgical incisions; pack into deep wounds	Alginate supports a moist wound environment; collagen component promotes cellular and vascular in-growth, as well as fibroblast proliferation, resulting in granulation tissue and neoepithelialization at the wound site	75 foot ulcer patients; 81% wound area reduction (61% control group); complete wound healing outcomes in 48% patients (compared with 36% in the control group)	220,283–286
Gintuit ■ Organogenesis Inc.	Allogeneic cultured keratinocytes and fibroblasts in bovine collagen	Level 2 Level 3	Secretes human growth factors and cytokines and contains extracellular matrix proteins; these factors are known to be involved in wound repair and regeneration.	Indicated for topical (nonsubmerged) application to a surgically created vascular wound bed in the treatment of mucogingival conditions in adults	MoA was not directly stated in peer-reviewed literature. Company claims that Gintuit grafting over vascular wound beds creates color and texture matched tissue for treating mucogingival conditions, without providing root coverage	Evaluated in two clinical studies in adults with insufficient gingival tissue; in each of the two studies, Gintuit was associated with an increase of at least 2 mm of gingival tissue in at least 50% of the study subjects	287–289
Grafix □ Smith & Nephew	Human placental membrane allograft; ECM (collagen, elastin, laminin, fibronectin), mesenchymal stem cells, and growth factors	Level 2 Level 4 Level 5	Includes MSCs in the collagen-rich ECM to enhance and improve wound healing in the clinical setting	Wound cover that can be used for the treatment of both acute and chronic wounds, including but not limited to DFUs, VLUs, pressure ulcers, burns, surgical incisions and dehiscence, pyoderma gangrenosum, and epidermolysis bullosa	MoA was not directly stated in peer-reviewed literature. Company claims National Institute for Health and Care Excellence found Grafix to have the highest overall effect with “no serious risk of bias.” Cryopreservation resulted in 80% cell viability within membrane post-thaw; cells and growth factors are integral components of the membrane ECM, where MSCs were presumed to have most beneficial effects in wound healing in elderly patients.	Complete wound closure at 12 weeks in 62% of the patients with chronic DFU	290–295
GraftJacket ■ Stryker	Cadaveric skin collagen-based allograft; allogeneic cultured keratinocytes and fibroblasts in bovine collagen; elastin, collagen, hyaluronan, fibronectin, blood vessel channels	Level 2 Level 3 Level 5 Level 6b	GraftJacket can be used to provide supplemental support, protection, and reinforcement of tendon and ligamentous tissues, or other homologous use	Repair or replacement of damaged or inadequate integumental tissue, such as diabetic foot ulcers, venous leg ulcers, pressure ulcers, or for other homologous uses of human integument; rotator cuff injuries; Achilles tendon repair	Acellular scaffold promotes new cellular in-growth that developed a remodeled tendon-like structure 6 months postsurgery; acellularity makes graft less immunogenic; intact collagen ECM strengthens graft; intact blood vessel channels support revascularization and cellular infiltration to promote graft healing	Acellular human dermal matrix augmentation of large (>3 cm) cuff tears involving 2 tendons showed better ASES and Constant scores and more frequent intact cuffs as determined by gadolinium-enhanced magnetic resonance imaging (MRI); intact repairs were found in 85% of the augmented group and 40% of the nonaugmented group; no adverse events related to the acellular human dermal matrix were observed	296–299
NeuraGen Nerve Guide □ Integra LifeSciences	Nerve conduit; bovine type 1 collagen tube	Level 2 Level 4 Level 5 Level 7a Level 7b	Biocompatible ultra-pure collagen that allows for controlled resorption; the conduit’s precisely engineered porosity supports natural nerve regeneration by allowing nerve growth factors and Schwann cells to infiltrate	Indicated for the repair of peripheral nerve discontinuities where gap closure can be achieved by flexion of the extremity.	Provides a protective environment across nerve discontinuities, as well as an isolated conduit environment guiding axonal regrowth; has been used safely as a nerve graft seeded with MSCs to further promote motor nerve regeneration	Recovery of sensory and motor functions using collagen conduits was equivalent to direct suture at 24 months after repair when nerve gap inside tube was 6 mm or less; NeuraGen conduit repair also resulted in 40% less time in or than direct suture-repair	300–304
NuShield Organogenesis Inc.	Dehydrated human placental allograft with growth factors, ECM proteins (collagen type I, III, and high levels of IV, V, and VI), elastin, glycoproteins, proteoglycans including hyaluronic acid, dermatan sulfate, and chondroitin sulfate	Level 2 Level 5 Level 7b	Acts as an adjunct to soft tissue healing with excellent regenerative, anti-inflammatory, and angiogenic properties	Direct application in wrapping or suturing around tendons; on-lay graft to protect tendons, nerves, spine adhesions and fibrosis, acute and chronic wounds	Cytokines and growth factors (EGF, PDGF, transforming growth factor-β [TGF-β], bFGF) released from graft are chemotactic for keratinocytes and fibroblasts, promoting migration and proliferation; paracrine signaling following exposure to NuShield results in expression changes in keratinocytes and fibroblasts for genes that are mitogenic, regulate inflammation, or regulate proliferation	48% greater probability of wound closure in favor of the dACM (NuShield) group	305–309
Permacol □ Medtronic	Crosslinked porcine dermal collagen surgical mesh	Level 2 Level 3 Level 4 Level 5 Level 7a	Combining the tensile strength of synthetic hernia repair materials with the biocompatibility of an acellular porcine dermal implant; surgical implant delivers proven durability and strength for ventral hernia repair and abdominal wall reconstruction	Support and reinforce soft tissue in surgical procedures including rectal intussusception, congenital diaphragmatic hernia, and abdominal wall hernia repair	Crosslinking is introduced into the structure, making it resistant to the collagenase enzymes responsible for the breakdown and resorption of implanted collagen; crosslinking also protects against bacterial degradation; postimplantation there is an acute inflammatory response that facilitates infiltration and healing; angiogenesis produces capillary ingrowth; implant gradually becomes permanently incorporated into the tissue with well-organized collagen and skeletal muscle	Permacol mesh in BioLIFT is feasible and achieves a high primary healing rate of 80%; trend of lower recurrence rates than competitors	310–319
PriMatrix and PriMatrix Ag Dermal Repair Scaffold □ Integra LifeSciences	Acellular fetal bovine dermis sheet; type III collagen; PriMatrix Ag contains silver	Level 2 Level 3 Level 4 Level 5 Level 7b	Provides an environment that supports cellular repopulation and revascularization; the silver in PriMatrix Ag is intended to prevent microbial colonization of the device	Indicated for management of wounds including: partial and full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, second-degree burns, surgical wounds, trauma wounds, tunneled/undermined wounds, and draining wounds; not indicated for third degree burns	Has biocompatibility as well as the ability to trap and bind the patient’s own cells and growth factors within the porous matrix at the time of surgery; implants trigger an initial inflammatory cell infiltrate followed by migration of mesenchymal cells and neovascularization; progressive remodeling by host cell infiltrates replaces graft tissue with histologically normal-appearing host tissue	In a prospective multicenter study, 76% of patients treated with PriMatrix for management of diabetic foot ulcers achieved closure by 12 weeks; a retrospective case series of 43 consecutive partial- or full-thickness wounds treated with either PriMatrix or PriMatrix with negative pressure wound therapy showed that 88.3% of cases achieved wound closure through re-epithelialization of the dermal scaffold	320–329
Promogran Prisma □ Johnson & Johnson	55% collagen, 44% ORC, 1% silver with 25% w/w ionically bound silver (Promogran ORC +Ag)	Level 2 Level 4 Level 5 Level 7b	In the presence of exudate, matrix transforms into a soft, confirmable, biodegradable gel, and thus allows contact with all areas of the wound; the dressing helps create a moist wound bed and an environment that supports wound healing; addition of silver provides antibiosis to chronic wounds	Indicated for the management of exuding wounds including: pressure injuries, diabetic ulcers, venous ulcers, ulcers caused by mixed vascular etiologies, partial- and full-thickness wounds, donor sites and other bleeding surface wounds, abrasions, traumatic wounds healing by secondary intention, and dehisced surgical wounds	Reduces MMPs and free radicals in wounds; removes excess metal ions; protects growth factors and proteins that promote wound healing and tissue formation	Randomized controlled trial demonstrated that collagen/ORC/silver treatment significantly increased healing compared with the control treatment, using healing criteria of 50% reduction in wound area by week 4	330–334

Collagen-based products levels of evidence. Level 2 = 1 well-designed RCT/multi-site study; Level 3 = clinical studies—observational/mechanism of action (MoA); Level 4 = historical cohort (retrospective) or case-control studies (retrospective with control group); Level 5 = other clinical studies (case series or studies as reference treatment, human ex vivo MoA); Level 6a = large animal with MoA; Level 6b = large animal observational; Level 7a = small animal with MoA; Level 7b = small animal observational and in vitro.FDA status: □ - cleared; ■ - approved.

Other collagen products used in oral surgery are applied to cover socket void fillers as a membranous sheet. For example, a non-crosslinked bilayer collagen membrane osteophilic matrix (Bio-Gide) has a film layer designed to prevent soft tissue invasion into the socket, thus promoting alveolar ridge preservation and bone regeneration.^133,504 A comparable product with a sugar crosslinked collagen membrane (Ossix Plus) prevented host cell infiltration⁴⁰⁹ (Tables 1, 5). The noncrosslinked structure of collagen membranes (Bio-Gide) promoted angiogenesis and vascularization in the wound; whereas cross-linked collagen membranes (Ossix Plus) were not permissive for angiogenesis, yet still allowed nutrient permeation.⁴¹⁰ Filling extraction sockets with deproteinized bovine bone mineral and 10% porcine type 1 collagen (Bio-Oss) prior to sealing with extraction sockets with noncrosslinked bilayer collagen membrane (Bio-Gide) significantly improved bone height and width preservation for 6 months postextraction.¹³³ The use of collagen products singly, or in combination, can preserve alveolar bone which otherwise would undergo the healing-induced remodeling and volumetric loss of socket contour post-tooth extraction.¹³³ Thus, use of these collagen products may preserve alveolar ridge necessary for subsequent dental implants without the need for additional bone grafting.

Table 5.

Level of evidence 5

Dressing	Composition	Level of evidence	Purpose/Claim	Use	Mechanism of action	Outcomes study/Trial	References
Biostep and Biostep AG □ Smith & Nephew	Semi-denatured cross-linked porcine collagen, EDTA, alginate, silver, carboxylmethylcellulose (CMC)	Level 5	Collagen binds excess MMPs while EDTA irreversibly deactivates MMPs; alginate component to absorb a high level of moisture; antibacterial activity of silver to help maintain bacterial balance for contaminated and colonized wounds	Management of full-thickness and partial-thickness acute and chronic wounds including: pressure injuries, diabetic ulcers, ulcers caused by mixed vascular etiologies, venous ulcers, first-, and second-degree burns, donor/graft sites, abrasions, dehisced surgical wounds, and traumatic wounds healing by secondary intention	Crosslinked collagen attracts MMPs so the dressing, and not native collagen, is degraded; EDTA binds zinc to deactivate MMPs; antimicrobial activity of silver ions to inhibit microbial ingress of the dressing and maintain bacterial balance; maximum surface area of collagen dressing, CMC, and physiological pH allows maximum exudate absorption and promotes wound healing	Enhanced granulation, tissue regeneration, and epithelialization were achieved within a relatively short time period (1–2 weeks); a patient presented with a lateral malleolus ulcer secondary to minor trauma that had failed to respond to 4 weeks of conventional wound care. Biostep dressing was applied, and the wound had nearly closed by 21 days of treatment.	389–391
CollaTape ■ Zimmer Biomet	Type 1 bovine tendon-derived collagen	Level 5 Level 7b	Control bleeding and stabilize blood clots as well as protect the wound bed while accelerating the healing process; porous, absorbable matrix supports delicate new tissue	Intended for localized ridge defects, socket grafting, oral ulcers (noninfected or viral), periodontal surgical wounds, burns	Rough surface, hydrophilicity, and sponge-like structure of collagen promotes osteoblast adhesion, mediated by osteoblast surface fibronectin; newly remodeled bone mass has been mainly attributed to type I collagen-driven angiogenesis; long term ridge preservation following tooth extraction is limited due to Collatape degradation within 5 weeks	Membrane permitted palatal fibroblast and epithelial cell adhesion, proliferation, and distribution which led to formation of mucosa-like tissue	248,392–395
Endoform □ Aroa Biosurgery, Ltd.	Natural dermal template; 90% intact native collagen, 10% ECM components: ovine forestomach, collagen type I, III, IV, elastin, GAGs, proteoglycans, FGF, laminin, fibronectin	Level 5 Level 7b	Rehydrated with exudate or sterile saline, the dermal template transforms into a soft conforming sheet, which is naturally incorporated into the wound over time; retains the native extracellular matrix-associated macromolecules, including fibronectin, glycosaminoglycans, laminin, and elastin; broad-spectrum MMP reduction	Intended for Hidradenitis suppurativa-chronic inflammatory skin disease, pressure ulcers, diabetic foot ulcers, surgical wounds, tunneling, and traumatic wounds	Provides a natural porous bioscaffold for rapid cell infiltration while reducing excess MMP; contains >150 ECM proteins and residual vascular channels to support the establishment of new vasculature	Wound dimensions decreased in 21 of 24 wounds, including patients with multiple comorbidities	396–398
FACIALGAIN Sunmax Biotechnology	Crosslinked porcine collagen implant with lidocane	Level 5 Level 6b	Crosslinked porcine collagen dermal filler injections can serve as a minimally invasive approach to enhance skin laxity	Dermal filler injections for treating dermatochalasis and periorbital hyperpigmentation; collagen implants for dermal contour correction.	MoA was not directly stated in peer-reviewed literature. Company claims glutaraldehyde cross-linking of collagen fibers increases the product stability and mechanical properties, while lidocaine is added to mitigate pain	Tissue in-growth was observed in the RPC constructs along with neovascularization and granulation tissue; at the 6-month time point, the RPC implant material blended somewhat imperceptibly with native, pre-existent collagen and accurate reaction zone measurements of the implant and associated host tissue response could not be made	399–402
Gentrix Surgical Matrix □ Integra LifeSciences	Porcine UBM sheet	Level 5 Level 6a Level 6b	Provides mechanical reinforcement; facilitates the body’s ability to remodel site-appropriate tissue	Implantation to reinforce soft tissue where weakness exists in patients requiring gastroenterological or plastic, reconstructive and urological surgery; some Gentrix devices are indicated to minimize tissue attachment to the device in case of direct contact with viscera	MoA was not directly stated in peer-reviewed literature. Company claims that Gentrix devices maintain an intact epithelial basement membrane and facilitates the body’s ability to remodel site-appropriate tissue	Retrospective case series of 64 patients who underwent complex ventral incisional hernia repairs (55% retrorectus and 44% intraperitoneal) reinforced with UBM; at the 36-month follow-up, there was a 15.6% recurrence rate and no cases of erosion, fistula formation, or need for mesh explantation; three patients had a full-thickness fascial biopsy which showed functional remodeling of site-appropriate connective tissue	403–408
Ossix Plus □ Dentsply Sirona	Porcine-derived type 1 collagen-based sugar cross-linked membrane	Level 5 Level 6a Level 7a Level 7b	Provides true barrier effect for 4–6 months, ossifies and contributes to improved long-term outcomes	Intended for use during the process of guided bone regeneration (GBR) and guided tissue regeneration (GTR) as a biodegradable barrier for: ridge augmentation for later implant insertions; simultaneous ridge augmentation and implant insertions; ridge augmentation around implants inserted in extraction sites; alveolar ridge preservation consequent to tooth extractions; over the window in lateral window sinus elevation procedure; implants with vertical bone loss due to infection, only in cases where satisfactory debridement and implant surface disinfection can be achieved; intra bony defects around teeth; treatment of recession defects, together with coronally positioned flap; in furcation defects in multi-rooted teeth	Promotes mineralized tissue formation around the site of implants; high cellular barrier function of cross-linked collagen and pepsin treatment (prevents host cell infiltration and reduces inflammation; membrane is still permissible for nutrient permeation	Membrane-protected site had formation of well-mineralized tissue at 12 weeks following exodontia, with minimal changes in alveolar ridge dimensions and no signs of membrane ossification	409–413
PSDV □ Baxter International Inc.	Peri-strip dry staple (PSD) line reinforcement with Veritas collagen matrix; dehydrated bovine pericardium vascular patch	Level 5	Increase the strength of staple-lines and/or reduce the risk of bleeding	Prosthesis for the surgical repair of soft tissue deficiencies using surgical staplers when staple line reinforcement is needed, including laparoscopic gastric bypass	Differs from traditional PSDs in that it is not crosslinked with glutaraldehyde; acellular collagen matrix promotes host fibroblast infiltration and capillary ingrowth; remodeling of this nonpermanent staple line buttress renders it indistinguishable from host tissues	The median duration of air leaks and median drainage time was significantly shorter in the PSDV group	151,414,415
Puracol □ Medline	Collagen wound dressing; 100% type 1 collagen with a high degree of nativity	Level 5 Level 7b	Jump-starts the wound healing process, making it ideal for wounds that are chronic or stalled; high gel integrity	Ideal for pressure, venous, diabetic ulcers, partial- and full-thickness wounds, ulcers caused by mixed vascular etiologies, burns, donor sites, and other surface wounds, scalp reconstruction, abrasions, traumatic wounds healing by secondary intention and dehisced surgical wounds	MoA was not directly stated in peer-reviewed literature. Company claims that Puracol retains triple-helix structural stability that persists in contact with liquid and aids in wound bed preparation for subsequent skin substitute; fragile collagen laminas within Puracol are reduced to thin collagen fibrils cross-linking wider collagen bundles of fibers, possibly making them inaccessible to collagenase; interaction with lymphocytes showed no appreciable difference in collagen matrix, contributing to matrix resilience during host cell infiltration; porosity of 80% promotes host cell infiltration and adhesion, which aids in wound healing	Can be tethered to antimicrobial peptides (AMP); collagen-tethering of AMPs without the harmful side effects of current approaches (e.g., bacterial resistance, general toxicity, scarring) and utilizing their wound healing functionality have important implications for the future of tethered AMPs	221,416,417
Puracol Plus and Puracol Plus Ag □ Medline	Collagen dressing with microscaffold; 100% type I native bovine collagen; Puracol Plus Ag+ contains hydrated silver chloride	Level 5 Level 7b	Helps jump-start stalled or chronic wounds when antimicrobial properties of silver are desired and help promote natural healing; Puracol Plus Ag+ silver adds antimicrobial properties	Indicated for pressure, venous, diabetic ulcers, partial- and full-thickness wounds, ulcers caused by mixed vascular etiologies, first- and second-degree burns, donor sites and other surface wounds, abrasions, traumatic wounds healing by secondary intention, and dehisced surgical wounds; solution for tunneling wounds that are difficult to dress because of the tendency of nonbiodegradable dressing materials to be retained in the wound even after their attempted removal	MoA was not directly stated in peer-reviewed literature. Company claims that Puracol Plus retains triple-helix structural stability that persists in contact with liquid and aids in wound bed preparation for subsequent skin substitute; triple helix collagen structure binds MMPs, resolving inflammation and supporting proliferation; hydrated silver chloride provides antibacterial properties	Increased rates of healing were found in the xenograft-treated (Puracol Plus) wounds as compared with previous studies of calvarium-exposed wounds healed by second intention alone; advantages of animal-derived collagen xenografts include immediate coverage of the wound, simple application, low cost, and avoidance of the morbidity associated with local flap, graft, and free flap repairs	221,341,418,419
RCM6 (resorbable collagen membrane) ■ ACE Surgical Supply	Tendon-derived type 1 bovine collagen; formaldehyde crosslinking	Level 5 Level 7a	Guides healing and regeneration of bone and surrounding tissue	Intended to aid in the wound-healing process of surgical procedures such as dental implants, bone and periodontal defects, and ridge augmentation	When used in conjunction with a bone-grafting particulate, it helps mitigate the migration of the particulate from the surgical site; fully resorbable with a resorption time of up to 6 months; integration of membrane by proliferating soft tissue, stabilization of blood clot, and host cell adhesion to membrane promote soft tissue healing	RCM6 remnants were seen in the biopsy specimen, an expected observation given that the reported resorption time is 6 months or more	420–423
Simpurity □ SNS Medical	Wound dressing collagen particles; 100% nonbleached, native undigested bovine collagen (Sold in combination packet: Total Wound Care Solution System [TWCSS] for clinical use)	Level 5	Flexible application for wounds of different sizes and shapes; medical grade, lyophilized bovine collagen is a clean, white powder; reduces inflammation and supports tissue healing; can be used as a hemostatic dressing	Medical-grade bovine collagen comes in a clean, white powder form, making it easy to apply directly to wounds; collagen powder helps reduce inflammation and supports the healing process by providing a substrate that diverts matrix metalloproteinases (MMPs) digestion away from healing tissues; can be used as a hemostatic dressing to control bleeding.	MoA was not directly stated in peer-reviewed literature. Company claims the porous structure provides excellent absorption and scaffolding for cell proliferation and migration	Improved wound healing in patients with chronic recalcitrant wounds, infected wounds, and comorbidities	424
Stimulen □ Southwest Technologies Inc.	Collagen gel wound dressing; 52% collagen of long and short polypeptides along with glycerin, water, fragrance	Level 5 Level 6a Level 7a	Can be used in emergency situations not only to cover a wound but also to fill cavity wounds; gel is convenient to use, especially in places that are difficult to apply the powder form, such as the bottom of a foot	Intended for partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, donor sites and other bleeding surface wounds, abrasions, trauma wounds, and first- and second-degree burns	Serves as a substrate for high MMPs in chronic wound environment; induces polarization of healing-like macrophages in the wound, which produce anti-inflammatory and pro-angiogenic responses and promote wound healing	On day 7, histological analysis showed significant increase in the length of rete ridges, suggesting improved biomechanical properties of the healing wound tissue; modified collagen gel significantly accelerated neutrophil and macrophage recruitment to the wound site on day 3 and day 7 with successful resolution of inflammation on day 21	33–35,425
Stimulen Powder □ Southwest Technologies Inc.	Collagen powder; hydrolyzed modified collagens, prepared polypeptides	Level 5	When sprinkled in the wound, it interacts with exudate to form a protective gel on the wound bed; gel protects new cells and tissue from dehydration; nonadherent; does not need to be removed from the wound site; the collagen powder is readily broken down by the natural enzymes present in most wound fluids	Management of wounds including: partial- and full-thickness wounds, pressure injuries (stages I–IV), venous ulcers, diabetic ulcers, partial-thickness burns, acute wounds, abrasions, traumatic wounds healing by secondary intention, and donor sites and other surface wounds	Forms a protective gel on the wound bed that prevents dehydration and provides a scaffolding to promotes cell proliferation and ECM deposition; hydrolyzed collagen forms a better hydrogel with peptides that promotes chemotactic signaling for host cell infiltration	Application of Stimulen collagen powder (applied once daily after wound cleansing) further supported tissue regeneration by providing a scaffold for cell growth and matrix deposition	426,427
Vergenix FG CollPlant Biotechnologies	Soft-tissue repair device; flowable gel; plant-derived recombinant human type I collagen (rhCollagen)	Level 5 Level 7b	Provides complete coverage, managing wound closure, offers a nonallergenic and a pathogen-free scaffold for safe and successful wound management	Chronic diabetic and venous wounds, pressure ulcers, traumatic injuries, and surgical wounds	Plant-derived human collagen. Scaffolds support primary human cell attachment and proliferation at an equivalent or higher level than bovine material; mixing with saline forms a collagen-fibrin matrix that enhances cell migration and tissue repair; promotes keratinocyte migration and proliferation that coincide with re-epithelialization; inflammation increased at day 1 and decreased by day 6, the induction and resolution of which helps drive the healing process	After 2 weeks of treatment, wound dehiscence was replaced with granulation tissue, and after 4 weeks, the patient was completely healed, with an acceptable aesthetic outcome of the surgical scar	428–432
Woun’Dres □ Coloplast	Collagen hydrogel; contains polymers including carbomer and collagen; other ingredients including allantoin	Level 5	Rehydrates dry wounds and eschar; promotes moist wound environment and autolytic debridement; latex-free	Intended for dry wounds, pressure ulcers, pressure wounds, pressure sores stages II–IV, venous stasis ulcers, superficial scrapes, second- and third-degree burns, partial-thickness and full-thickness wounds, tunneling wounds, infected wounds, exuding wounds, deep cavity wounds	Dressing rehydrates dry wounds and eschar; promotes moist wound healing environment and autolytic debridement; suppress inflammation and apoptosis	Dressing promoted full-thickness excisional wound healing with scar formation; immune cell accumulation was identified in the remaining biomaterials in the wound bed	433,434

Collagen-based products levels of evidence. Level 5 = other clinical studies (case series or studies as reference treatment, human ex vivo MoA); Level 6a = large animal with MoA; Level 6b = large animal observational; Level 7a = small animal with MoA; Level 7b = small animal observational and in vitro. FDA status: □ - cleared; ■ - approved.

COLLAGEN AS DIETARY SUPPLEMENT

The greatest proportion of collagen products currently resides with the food industry, reaching just over 55% of the total U.S. collagen market in 2024, followed by medical products. The food industry use of collagen shows up in a variety of forms from the casings around sausages, to thickening agents such as gelatin that are used to increase viscosity or as a way of regulating flavor release.^505,506 Collagen is also used in the food preservation industry to prevent water loss from meat during freezing/thawing and even shows up in ice cream products to prevent ice crystal formation. With such a large portion of the multi-billion-dollar collagen market being dedicated to the food industry, an important question comes to the forefront: Is collagen beneficial to eat?

Collagen supplements are showing up in food and beverage products across the globe, with claims of a variety of health benefits (Fig. 2). Predominantly found in connective tissues such as skin, cartilage, and bone, cartilage is recognized as source of fiber and protein. Protein Digestibility-Corrected Amino Acid Score evaluation following World Health Organization guidelines marks collagen as an incomplete protein source because of lack of tryptophan. Even so, peptides can substitute up to 36% of the daily protein requirements in the Western diet.⁵⁰⁷ This means that, while collagen cannot be used as a complete protein substitute, it may be a safe dietary supplement when used up to approximately one-third of a mixed protein diet.

One of the common health benefits advertised for ingested collagen products is healthier, more elastic skin with reduced wrinkle lines. It is unclear, however, what direct mechanisms of action may be responsible for these proclaimed benefits. There have been studies that make correlations between ingesting collagen bioactive dipeptides (Pro-Hyp and Hyp-Gly) or tripeptides (Gly-X-Y) and increased skin water content.^508–511 There is also evidence that oral ingestion of collagen peptides increases natural moisturizing factors in the stratum corneum including urea, lactic acid, filaggrin-derived amino acids, pyrrolidone carboxylic acid, and urocanic acid.^512,513 However, these observations did not show that ingestion of bioactive collagen peptides have an effect on collagen production, or retention of native collagen, within the skin.

Randomized controlled trials (RCTs) have shown that the ingestion of collagen hydrolysates and hydrolyzed collage-based supplements have a beneficial effect on wound healing for patients with burn wounds or pressure ulcers, respectively.^514,515 More recently, collagen peptides administered in combination with omega-3 fatty acids have been suggested as oral supplements with the potential to improve inflammatory responses and dysbiosis in burn patients. An RCT was performed on burn patients to determine if ingested collagen peptides were beneficial to regulate gut microbiome colonization, acting as a preventative treatment for dysbiosis. Patients did not, however, have any significant changes in Lactobacillus, Enterobacteriaceae, or F. prausnitzii concentrations between treatment groups.⁴⁴⁷ The mechanism for how ingested collagen is utilized for therapeutic benefit in wound healing or skin elasticity has not yet been defined, yet there are still strong correlative findings in experimental trials.^{475,514–516} Rigorous scientific studies are needed. It is unlikely that ingested collagen is incorporated directly, for example, into the dermis to supplant and replace regions of damaged or degrading collagen. It seems much more likely that once ingested, collagen is digested down to amino acids and short peptides that can circulate and be utilized by regenerative processes as base material for de novo collagen synthesis.

Oral collagen consumption has also been investigated for benefits independent of skin elasticity and wound healing. Ingestion of undenatured type II collagen can result in an oral immune tolerance response that can serve as a therapeutic treatment for autoimmune inflammatory disease, such as rheumatoid arthritis.⁵¹⁷ Oral immune tolerance can occur through multiple mechanisms, which begin with microfold epithelial cells (in Peyer’s patches of the gut-associated lymphoid tissue) transporting ingested antigens across the mucosal barrier.^518,519 Antigen presenting cells in the Peyer’s patches associate with T cells, which in turn circulate to mesenteric lymph nodes and, subsequently, to the peripheral immune system.⁵²⁰ T cells activated by type II collagen enter the blood stream and secrete anti-inflammatory cytokines TGF-β, IL-4, and IL-10 when in contact with articular cartilage.⁵¹⁸ This mechanism may result in a bystander effect that inhibits T helper (Th)1 response in arthritic lesions. Rigorous RCTs are required. Oral collagen has also shown potential benefits in cartilage degenerative conditions such as osteoarthritis. In a canine model of osteoarthritis, ingestion of undenatured type II collagen markedly reduced arthritic pain through a mechanism of action independent from glucosamine hydrochloride and chondroitin sulfate.⁵²¹ In a clinical trial, osteoarthritis patients receiving undenatured type II collagen oral doses over a 12-week period exhibited significant improvement in knee flexibility and mobility as well as reduced knee and back pain.⁵²² This same principle has held true in clinical studies with healthy individuals that have activity-related joint discomfort. Treatment with undenatured type II collagen oral supplements resulted in improved knee joint range of motion flexibility and extensibility.⁵²³

Oral consumption of enzymatically decomposed collagen peptides and tripeptides have also been correlated with improvement in hair condition (Fig. 3). In ex vivo human culture and in vivo animal models, oral collagen peptides activated the tissue homeostasis regulating canonical Wingless-related integration site (Wnt) (Wnt/glycogen synthase kinase-3 β/β-catenin) signaling pathways and stimulated growth factor (insulin-like growth factor binding protein-6, PDGF-AB, placental growth factor, VEGF, keratin27, Gprc5d, Ki67) expression.^524,525 This mechanism was associated with proliferation of human dermal papilla and outer root sheath cells, as well as human hair follicle elongation and increased hair growth. While this mechanism has not been shown in patients, it does provide insight into collagen peptide signaling mechanisms and the broader range of impacts oral collagen supplements may have in the body. These findings are promising but not definitive. Rigorous clinical studies are required.

When considering oral undenatured type II collagen supplements for personal therapeutic use, it is worth noting that not all products are created equal. Physiochemical and analytical characteristics can differ between products, with appreciable differences in color, coarseness, molecular size, and proportion of undenatured collagen to hydrolyzed collagen peptides per dose.⁵²⁶ These differences can be attributed to the mechanical processes and milling approaches used by the manufacturer.⁵²⁷ The difference in undenatured collagen per dose could have direct effects on pharmacological therapeutic benefit. Collagen as an oral supplement or therapeutic is not harmful and has several potential health-related benefits for malnutrition and inflammatory joints. However, specific uses for oral collagen supplements can often be overshadowed or sensationalized by media and advertising that boast outcomes that are not supported by rigorous science.⁵²⁸

FUTURE PERSPECTIVES

By 2030, collagen will no longer be seen as just a cosmetic ingredient—it will be a cornerstone of regenerative medicine and personalized health care. The transformation is already underway.

Wound Healing: From Passive Dressings to Bioactive Therapies: Companies are pioneering the next generation of wound care with collagen-infused calcium alginate dressings that not only protect wounds but actively accelerate healing.^529,530 These dressings maintain a moist environment, reduce scarring, and are increasingly used outside hospital settings—empowering patients to manage recovery at home. Products enriched in specific hydrolysis of collagen will serve wound dressing functions with outcomes far superior to anything we know of today. Hydrolyzed collagen hydrogels, nanofibers, and sponges will promote angiogenesis, reduce inflammation, and stimulate tissue regeneration.^529,531 These materials are being tailored for chronic wounds, burns, and surgical recovery, with smart dressings on the horizon that can release drugs or signal infection in real time.^532,533

Skincare: From Anti-Aging to Skin Regeneration: In the consumer space, collagen is evolving from a buzzword to a bioactive ingredient with clinically validated benefits. Topical formulations are being enhanced with collagen peptides, encapsulated delivery systems, and synergistic compounds like HA and vitamin C to improve skin elasticity, hydration, and repair.^{474,534–536} The next frontier is personalized collagen skincare, where products are tailored to an individual’s skin microbiome, genetic profile, and environmental exposures.^537,538 Artificial intelligence-driven diagnostics and 3D skin printing may soon allow consumers to “print” collagen patches at home for targeted treatment.^539–541

Healthcare and Regenerative Medicine: Beyond skin, collagen is being integrated into tissue scaffolds, injectable fillers, and implant coatings to support healing in joints, bones, and internal organs.^{121,382,542–544} Innovations in recombinant collagen production and production of hydrolyzed collagen active principles—using yeast, bacteria, or even plants—are making it safer, more sustainable, and customizable for medical use.^545–547 In the near future, collagen-based biosensors may monitor healing progress or detect early signs of infection.^532,548 Combined with wearable tech, this could revolutionize postoperative care and chronic disease management.

Sustainability and Ethical Sourcing: As demand grows, the industry is shifting toward non-animal sources of collagen, including marine collagen and lab-grown alternatives.^{61,77,545,546} These options reduce the risk of disease transmission, align with ethical consumer values, and open doors for vegan-certified products.

ACKNOWLEDGMENTS AND FUNDING SOURCES

The authors thank the 13 peer reviewers for their critical comments that were helpful in improving this work. Relevant work in C.K.S. laboratory is supported by grants awarded to C.K.S. as PI by the U.S. Department of Defense [Grants MTEC/2019-447, MTEC/2021-425]; the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Grants DK119099, DK125835, DK128845, DK135447, DK143282, DK141513]; and the Biotech 2023–2024 PACommonwealth BT McGowan Grant.

Table 4.

Level of evidence 4

Dressing	Composition	Level of evidence	Purpose/Claim	Use	Mechanism of action	Outcomes study/Trial	References
BriDGE □ Harbor MedTech	Stabilized acellular equine pericardial collagen matrix (sPCM) wound care dressing	Level 4 Level 5 Level 6a Level 7a	Proteolytic enzyme degradation resistant, fully flexible cross-linked tissue that may be used as wound care dressing; a safe and beneficial treatment for neuropathic wounds; accelerates wound healing and reduces biofilm formation	Neuropathic foot wounds, difficult-to-treat and recalcitrant wounds of the lower extremity including diabetic, venous, trauma, vasculitic, and postsurgical wounds	Primary transient inflammatory response followed by wound healing; antimicrobial and antibiofilm properties; enhanced epithelialization and collagen deposition and maturation that promote wound healing	Closed wounds twice as fast as the published results of other skin substitute products; did not require weekly re-application	44,375–377
Cytal Wound Matrix/MicroMatrix UBM Particulate □ Integra LifeSciences	Porcine urinary bladder matrix (UBM) sheet/porcine UBM particulate	Level 4 Level 5	Enables a shift from an inflammatory wound environment into one that facilitates cellular infiltration and fast formation of site-appropriate, vascularized tissue	Cytal Wound Matrix: indicated for the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds; not indicated for third-degree burns. MicroMatrix UBM Particulate: indicated for the management of wounds including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds, trauma wounds, and draining wounds	MoA was not directly stated in peer-reviewed literature. Company claims that Cytal Wound Matrix: Supports a shift from an inflammatory wound environment into one that facilitates cellular infiltration and fast formation of site-appropriate, vascularized tissue MicroMatrix UBM Particulate: Supports a shift from an inflammatory wound environment to one that facilitates rapid revascularization to support wound closure	A prospective case control study assessed wound management with UBM which showed a statistically significant decrease in M1 to M2 scores for both diabetic and nondiabetic patients, which correlated with the rate of wound area reduction; a case series that addresses the utilization of UBM products (both Cytal and MicroMatrix) in a surgical care algorithm for combat injuries in 51 cases; in 86% of cases, there was successful granulation tissue formation or preparation of the wound bed for secondary DRT placement, skin grafting, or flap coverage	378–381
Healos □ DePuy Synthes	Bone graft substitute; mineralized collagen bone matrix; type 1 bovine collagen and hydroxyapatite particles (strips/pads)	Level 4 Level 7a Level 7b	Provides a bone void filler that is resorbed and remodeled into bone as part of the natural healing process	For use in filling bony voids or gaps that are not intrinsic to the stability of the bony structure; substitute for autologous iliac crest bone graft when used in fusion procedures of the lumbar spine	Healos loaded with connective tissue growth factor (CTGF) and mesenchymal progenitor cells produce progeny cells that differentiate into osteoblasts and osteocytes, which can bridge the bone defect and retained a large marrow compartment	21 patients were included and all patients achieved successful fusion; computed tomography scans showed solid bilateral fusion with bridging bone (Grade I) in all patients, but solid unilateral fusion with bridging bone (Grade II) was detected for one patient at one level	382–385
SurgiMend Collagen Matrix □ Integra LifeSciences	Acellular fetal bovine dermis sheet	Level 4	Implantation to reinforce soft tissue where weakness exists and for the surgical repair of damaged or ruptured soft tissue membranes	Indicated for plastic and reconstructive surgery, muscle flap reinforcement, hernia repair including abdominal, inguinal, femoral, diaphragmatic, scrotal, umbilical, and incisional	MoA was not directly stated in peer-reviewed literature. Company claims that SurgiMend supports rapid revascularization and integrates with host tissue for a durable, mechanically robust repair	A retrospective case series of a single surgeon’s experience with abdominal wall reconstruction with reinforcement using Surgimend showed no recurrence in 93% of patients at 18 months, which was significantly better than the authors previous outcomes in a prior series where Surgimend was not used	386–388

Collagen-based products levels of evidence. Level 4 = historical cohort (retrospective) or case-control studies (retrospective with control group); Level 5 = other clinical studies (case series or studies as reference treatment, human ex vivo MoA); Level 6a = large animal with MoA; Level 6b = large animal observational; Level 7a = small animal with MoA; Level 7b = small animal observational and in vitro. FDA status: □ - cleared; ■ - approved.

TAKE HOME MESSAGES.

1. Wound Healing and Collagen-Based Products

   • Collagen is the dominant structural protein (25–30% of total body protein), with types I and III being most abundant in skin (80–85% and 8–11%, respectively).⁵⁴⁹
   • Mechanisms of Action
   • Historical Milestones:

     • 1981: First commercial collagen dressing (CollaDerm, Integra LifeSciences).
     • 1985: Instat (collagen sponge for hemostasis, J&J).
     • 1996: Integra dermal regeneration template (DRT) (collagen-GAG template for burns).
     • 2000: ColActive (bovine collagen dressing by SouthWest Technologies).
     • 2002: Promogran (collagen-cellulose matrix for chronic wounds, J&J, now Solventum).
   • Mechanisms of Action

     • Provides scaffold for tissue growth, reduces inflammation, maintains moist wound environment.
     • Regulates mechanisms associated with diabetic ulcers, venous stasis ulcers, and pressure ulcers.
2. Collagen-Based Dressings and Innovations

   • Types of Collagen Dressings:

     • Films (adherent, for small wounds)
     • Sponges (absorbent, for high-exudate wounds)
     • Hydrogels (moisture-retentive, nonadherent)
     • Powders (for exudate absorption)
     • Acellular scaffolds (e.g., fish skin grafts—low immunogenicity).
   • Emerging Technologies

     • 3D-printed collagen skin (Pandorum Tech).
     • Recombinant human collagen (CollPlant’s plant-based rhCollagen).
     • Phage-integrated dressings (target MRSA/Pseudomonas).
3. Regenerative Medicine and Skin Substitutes

   • Skin Substitutes:

     • Dermagraft (living fibroblast scaffold) and Integra DRT (collagen-GAG matrix) improve healing in burns/diabetic ulcers.
     • Growth factor–collagen combos (e.g., VEGF + collagen) enhance angiogenesis.
   • Cardiovascular:

     • Collagen-coated vascular grafts (e.g., Dacron) show >90% patency at 8 years
     • Injectable collagen hydrogels support post-heart attack repair.
4. Topical and Injectable Collagen

   • ⚠ Topical Collagen Does NOT Replace Skin Collagen

     • Large molecules cannot penetrate skin but may:

       • Hydrate (temporarily plumps skin)
       • Signal fibroblasts (via peptides like Gly-Pro-Hyp).
       • Provide antioxidant protection
   • Injectable fillers

     • Short-term effects (absorbed in 1–3 months)
     • Risks: Granulomas, necrosis, biofilm formation
     • Alternatives: Hyaluronic acid (lasts 12–24 months)
5. Orthopedics and Dental Applications

   • Tendon/Bone Repair

     • Acellular collagen scaffolds (e.g., GraftJacket) aid rotator cuff healing
     • Collagen + BMP promotes bone growth in spinal fusion/tibial defects
   • Dental Uses

     • CollaPlug: Reduces postextraction bleeding/pain
     • Collagen membranes (e.g., Bio-Gide) preserve alveolar bone for implants.
6. Collagen as a Food Supplement

   • Limited Protein Value

     • Incomplete protein (lacks tryptophan); max 36% of daily protein intake
     • Claimed Benefits: skin hydration (via peptides like Pro-Hyp), but no proven collagen synthesis
     • Joint health: Undenatured Type II collagen may reduce arthritis pain (oral tolerance mechanism).
     ⚠ Marketing Hype: Many claims lack rigorous clinical evidence.
7. Future Directions

   • Pipeline Innovations

     • Biosynthetic collagen (yeast/fermentation-derived)
     • Drug-eluting dressings (e.g., VEGF/PDGF-loaded collagen)
     • Artificial intelligence-monitored collagen scaffolds (Integra LifeSciences).

Abbreviations and Acronyms

ACL

anterior cruciate ligament

Ag

silver

AMP

antimicrobial peptide

ASES score

American Shoulder and Elbow Surgeons score

bFGF

basic fibroblast growth factor

BMA

bone marrow aspirate

BMP

bone morphogenic protein

CaHA

calcium hydroxyapatite

CMI

collagen meniscus implant

CTGF

connective tissue growth factor

CTP

collagen tripeptide

DFU

diabetic foot ulcer

DICAL

calcium phosphate, dibasic

DRT

dermal regeneration template

ECM

extracellular matrix

EDTA

ethylenediaminetetraacetic acid

FGF

fibroblast growth factor

FN1

fibronectin-1

GAG

glycosaminoglycan

GBR

guided bone regeneration

Gly

glycine

Gprc

G protein-coupled receptor

GTR

guided tissue regeneration

HA

hyaluronic acid

HDB-1

human keratinocyte β-defensin-1

IL

interleukin

MCP-1

monocyte chemoattractant protein-1

miR

microRNA

MMP

matrix metalloprotease

MoA

mechanism of action

MSC

mesenchymal stem cell

PAD

peripheral arterial disease

PDGF

platelet-derived growth factor

PEG

polyethylene glycol

PLLA

poly-L-lactic acid

PMMA

polymethyl methacrylate

pro-α

pro-alpha

Pro-Hyp

prolyl-hydroxyproline

PSDs

Peri-strip dry staples

RCT

randomized controlled trial

rhCollagen

recombinant human collagen

SIS

small intestinal submucosa

TGF-β

transforming growth factor β

UBM

urinary bladder matrix

UV

ultraviolet

VEGF

vascular endothelial growth factor

VLU

venous leg ulcer

Wnt

Wingless-related integration site

Biographies

Chandan K. Sen

Dr. Chandan K. Sen, PhD, FNAI, is a University Endowed Professor of Surgery at the University of Pittsburgh School of Medicine. He is the director of the McGowan Institute of Regenerative Medicine and serves as the Chief Scientific Officer of the UPMC Health System’s wound care service line. He has a Google Scholar H-index of 117. Dr. Andrew Friday, PhD, is a senior scientist at the McGowan Institute of Regenerative Medicine at the University of Pittsburgh School of Medicine. Dr. Savita Khanna, PhD, is a Professor at the at the McGowan Institute of Regenerative Medicine at the University of Pittsburgh School of Medicine. Her laboratory specializes on neurodegeneration and neuropathy with emphasis on rescue. Dr. Sashwati Roy, PhD, is a tenured Professor at the at the McGowan Institute of Regenerative Medicine at the University of Pittsburgh School of Medicine. Her program focuses on wound inflammation and biofilm infection. She is a principal investigator of the NIDDK-Diabetic Foot Consortium.