Collagen-based scaffolds have emerged as essential adjuncts in wound reconstruction and skin grafting. Their biological activity, structural support, and ability to modulate the wound microenvironment make them valuable for preparing graft beds, stabilizing grafts, and accelerating postoperative healing. This paper examines the biological functions of collagen scaffolds and their potential role in wound bed preparation for skin grafting.

Key Takeaways

• Collagen scaffolds provide a framework for cellular attachment and migration, support vascular ingrowth, and serve as a sacrificial substrate for excess proteases.
• In skin grafting, collagen scaffolds may help prepare a vascularized wound bed and support moisture balance, graft adherence, and early healing.
• Scaffold properties, including porosity, absorption capacity, conformability, and pH, vary by formulation and design and may influence tissue integration and wound fluid management.

Introduction

Historically, collagen has been used in the medical field since the late 19th century in “catgut” sutures introduced by Joseph Lister and William Macewen.¹ Since then, its modern applications in regenerative medicine began to make significant headway in the mid-20th century through its use in hemostatic agents and burn dressings.

Early wound dressings primarily provide served as a passive passive barrier, providing wound coverage and lack the biological activity necessary without actively modulating the wound environment. This has driven interest in bioactive scaffolds, such as collagen matrices, that actively participate in tissue regeneration.² Collagen scaffolds, particularly those composed of purified type I collagen, serve as temporary extracellular matrices (ECMs) that guide cellular migration, modulate protease activity, and support vascular ingrowth.³

Despite advances in reconstructive techniques, achieving optimal wound bed preparation and consistent graft uptake remains challenging, particularly in chronic wounds characterized by protease imbalance, bacterial burden, and impaired vascularization. 

Mechanism of Collagen-Mediated Wound Healing

ECM Support and Cellular Migration

Collagen scaffolds function as bioactive ECM analogues by providing both a structural framework and biological signals that support tissue repair. As the primary protein of the native ECM, collagen closely mimics the natural wound environment, creating a 3-dimensional framework that supports cell attachment, migration, and proliferation.^4,5 Cells interact with collagen through surface receptors known as integrins, which activate signaling pathways involved in wound healing and tissue regeneration.⁶

Collagen–cell interactions also play an important role in cellular migration. Fibroblasts adhere to the collagen scaffold and migrate into the wound bed, where they synthesize new ECM components and contribute to granulated tissue formation.^7,8 Furthermore, collagen scaffolds with higher porosity can significantly accelerate this process, as larger, interconnected pores provide less resistance to fibroblast migration and can support the diffusion of molecules that aid in cell regeneration.^9–11 

Angiogenesis and Tissue Regeneration

The collagen scaffold also guides the migration of keratinocytes and other reparative cells, facilitating wound closure and tissue remodeling. In addition, collagen supports angiogenesis by providing a substrate for endothelial cell attachment and migration.¹² Endothelial cells infiltrate the collagen matrix and form new capillary networks, improving the delivery of oxygen and nutrients to the healing tissue. Through these combined structural and biological functions, collagen scaffolds help coordinate the cellular activities necessary for effective wound repair.

Protease Modulation

Collagen also functions as a sacrificial substrate for excessive protease activity, particularly that of matrix metalloproteinases (MMPs), which are often elevated in chronic or nonhealing wounds.^1,13 In normal wound healing, protease activity is highly regulated and serves important roles in clearing debris and remodeling tissue.¹⁴ However, prolonged inflammation in a wound can lead to an overproduction of MMPs that outpaces naturally occurring inhibitors and results in degradation of the ECM.^15,16 In this role, exogenous collagen is preferentially degraded by proteases, effectively diverting enzymatic activity away from newly formed ECM components. This protease-modulating effect contributes to improved tissue stability and more efficient tissue repair.

Collagen Scaffolds in Skin Grafting 

Collagen scaffolds are used in a wide range of scenarios, from burns and necrotic wounds, which are common among patients receiving skin grafts, to chronic ulcers and traumatic defects. In each of these settings, clinicians may choose to use collagen to optimize wound bed preparation, support grafts, and assist with postoperative tissue maturation, especially in complex wounds for which traditional dressings may be insufficient because of their inability to manage exudate or facilitate the breakdown of large amounts of necrotic tissue. Collagen’s role as a sacrificial substrate can also help in wounds such as chronic ulcers, which typically involve prolonged inflammation and elevated protease activity that stall wound healing.¹⁷ 

Different types of collagen scaffolds exhibit varying porosity and absorption capacities, and modulation of these properties has demonstrated clinical effectiveness.^18,19 Additionally, creating a more acidic wound environment may provide further benefits in grafts involving necrotic or infected wounds, which may harbor higher bacterial burdens and thus benefit from a more hostile environment for bacteria. Maintaining a low-pH wound environment can promote healing by enhancing tissue repair and suppressing bacterial growth. For example, a study has found that treatment with acidic buffers, particularly at pH 4, accelerated wound healing by promoting faster epithelialization, greater wound closure, and increased collagen deposition compared to higher-pH buffers and untreated controls.^20,21 Incorporating low-pH properties into a scaffold may provide additional benefit by reducing microbial colonization within the collagen scaffold and thereby improving infection control.^20,21 

One such setting in which collagen scaffolds can be applied is skin grafting, a cornerstone of reconstructive surgery for burns, trauma, chronic wounds, and oncologic defects.^17,22 Successful grafting depends not only on surgical technique but also on the biological quality of the wound bed and the microenvironment that supports angiogenesis and tissue regeneration.²³

Preparing a wound for skin grafting is a dynamic process that evolves biologically and mechanically over time. As the wound progresses toward graft readiness, collagen scaffolds can support wound bed preparation by promoting the development of healthy, vascularized tissue suitable for eventual graft placement. 

Collagen scaffolds may be applied after surgical debridement to prepare the wound bed for successful graft acceptance. Their porous structure provides a biological scaffold that supports fibroblast migration and early granulation tissue formation. This helps move the wound from a prolonged inflammatory state toward a healing environment, creating a stronger foundation for graft placement.^22,24 Collagen scaffolds also help regulate the wound environment by binding excess proteases that can break down newly formed tissue and disrupt ECM remodeling. 

Collagen scaffolds act as temporary biologic dressings that may help stabilize split-thickness skin grafts (STSGs) and support early graft uptake. An STSG involves surgically harvesting the epidermis and a small portion of the underlying dermis from a healthy donor site to cover an open wound. However, applying the skin graft without properly preparing the wound bed may increase the risk of graft rejection, graft infection, and improper healing of the wound.

Preparing the wound bed with a collagen scaffold helps create a stable foundation for graft placement while allowing new blood vessels to grow into the tissue through neovascularization.²⁵

Once applied, a collagen scaffold can interact with wound fluid by absorbing and binding fluid within the matrix, forming a gel-like structure.²⁶ This helps the collagen scaffold maintain close contact with the wound bed and prevents it from drying out. This moisture balance supports important early healing processes, including plasmatic imbibition, graft adherence, and revascularization.

To further manage wound exudate, the physical design characteristics of collagen scaffolds, including pore size, scaffold dimensions, and thickness can be tailored to improve conformability, drainage, and tissue integration.^10,11 These properties vary depending on the scaffold design and manufacturing process. Such design modifications may allow collagen scaffolds to manage excess wound fluid, reducing the risk of fluid accumulation beneath the graft and helping maintain close contact between the graft and wound bed. Additionally, structural adaptations may improve matrix flexibility, enabling the scaffold to conform more effectively to irregular wound surfaces.

As the wound bed recovers, collagen scaffolds continue to support healing by maintaining a protected, moist, and pH-modulated environment that helps reduce bacterial growth and limit protease-mediated tissue breakdown.²⁰ They also promote angiogenesis and tissue ingrowth, supporting the development and stabilization of a well-vascularized neodermis suitable for eventual graft placement.²⁷

As healing progresses, the collagen scaffold is gradually resorbed and replaced by newly formed tissue, creating a more viable wound bed, ready for graft placement. Together, these processes can support successful graft uptake, efficient epithelialization, durable wound closure, and potentially contribute to reduced complication rates.

Conclusion

Collagen scaffolds provide multifaceted biologic advantages in preparing the wounds for skin grafting. Their ability to serve as a temporary ECM, modulate protease activity, and maintain a well-vascularized environment addresses several barriers to successful grafting. The absorption capacity, porosity, and pH of collagen scaffolds can be modified and optimized to improve tissue integration and promote a more ideal wound-healing environment. Collagen scaffolds demonstrate additional benefits due to its porous structure, which enhances conformability, hydration responsiveness, and mechanical stability. Collagen can play a critical role in modern skin grafting by contributing to optimizing the wound bed, stabilizing grafts, and accelerating postoperative healing. Its biologic activity, structural support, and microenvironmental modulation make position it as a valuable tool to consider in reconstructive surgery.

Pragya Kancherla is a research assistant at MPM Medical with an interest in medical research and the clinical applications of collagen in skin grafting and wound healing. She is committed to contributing to research that advances medical knowledge and clinical practice.

Dr. Bhavya Vaish is an R&D Engineer at MPM Medical, specializing in biomaterials development, collagen-based medical devices, and regenerative medicine. She earned her PhD in Bioengineering from the University of Texas at Arlington, where her research focused on musculoskeletal tissue repair and inflammation. Her work bridges biomaterials research and translational product development.

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