Non-Cellular Therapies

In regenerative medicine, while cellular therapies are the most widely recognized, there are equally effective alternatives that, according to some experts, may rival them and even offer a more accessible option with fewer complications. Below, we will review some of these therapeutic to

Platelet-Rich Plasma (PRP)

To begin, it is essential to clarify the difference between plasma and serum, as they are often confused. Plasma is the liquid fraction of blood obtained through centrifugation that retains coagulation factors, whereas serum is t

Platelets are anucleate cell fragments with an approximate concentration of 200,000 per microliter in peripheral blood. While traditionally associated only with coagulation, they are now recognized for their role in tissue repair and regeneration. Because of this, PRP is also known as platelet-rich growth factor (PRGF). Its mechanism of action lies in the release of bioactive factors that mediate inflammation, proliferation, and tissue remodeling following injury.

PRP is a preparation with a platelet concentration two to five times higher than circulating blood, making it a therapeutic option with the potential to stimulate regeneration in tissues with low vascularization and limited healing capacity. Since the 1980s-1990s, PRP has been used to treat muscle, tendon, ligament, and cartilage injuries. However, its effectiveness varies depending on preparation and application protocols.

To optimize its use, certain minimum criteria have been established for its preparation, such as:

• Leukocyte concentration below 1,000/mL: Reduces the risk of infection but may increase the inflammatory response, potentially affecting tissue recovery.
• Red blood cell concentration below 1,000/mL: Minimizes iron-induced cellular damage.
• Platelet activation: For intra-articular or bone-integration applications, activation with calcium gluconate or thrombin is recommended. In soft tissue applications, platelets can be naturally activated upon contact with tendon collagen, facilitating their integration and functionality in tissue repair.

Indications and Clinical Evidence

In sports medicine, PRP has been used for tendinopathies and osteoarthritis, though its indication must be carefully assessed. It is not recommended for patients with active infections, systemic immunosuppression, or those taking anticoagulants or antiplatelet agents.

The strongest scientific evidence supports its use in:

• Level 1A: Lateral epicondylitis, knee osteoarthritis, plantar fasciitis, and rotator cuff tendinopathies.
• Level 1B: Patellar tendinopathy and hip osteoarthritis.

Secretome

The secretome refers to the set of bioactive molecules secreted by cells into their extracellular environment, including proteins, lipids, nucleic acids, and extracellular vesicles. In the case of mesenchymal stromal cells (MSCs), the conditioned medium resulting from their laboratory culture contains a high concentration of these therapeutic factors.

Secretome Modulation

The composition of the secretome can be modified through genetic, chemical, or environmental stimuli, such as:

• Hypoxia induction (low oxygen concentration).
• Serum deprivation (nutrient reduction in the culture medium).
• Activation with inflammatory or apoptotic signals (programmed cell death without inflammation).

These techniques allow for directing secretion toward a specific profile of bioactive factors.

Properties and Applications

The secretome has demonstrated effects on various physiological processes, including:

• Immunomodulation and anti-inflammatory effects: Mediated by cytokines such as TNF-α, TGF-β, IL-1, IL-6, IL-8, and IL-10, which regulate T-cell activity.
• Angiogenic regulation: Promotes new blood vessel formation through VEGF, PDGF, and GM-CSF.
• Neuroprotection: Neurotrophic factors like BDNF, NGF, GDNF, and CNTF activate neuronal survival signaling.

The secretome derived from umbilical cord MSCs has shown potential for skin rejuvenation and wound healing by stimulating fibroblast and keratinocyte proliferation.

Compared to whole-cell transplantation, secretome-based therapies offer advantages such as a lower risk of infection, absence of tumorigenicity, and reduced immunogenicity.

Exosomes

Exosomes are extracellular vesicles ranging from 30 to 100 nm in diameter, derived from the endosomal pathway. They are present in the secretome of all cells, but those obtained from MSCs have demonstrated therapeutic effects in atopic dermatitis and tissue regeneration by promoting:

• Fibroblast proliferation
• Collagen synthesis and deposition
• Re-epithelialization and vascularization of wounds

The optimization of exosome production and their clinical applications will be explored in future publications.

Other Therapeutic Options

Additional, less-studied alternatives include:

• Placental protein extracts: Contain a low-molecular-weight alpha-lipoprotein that stimulates melanocyte proliferation, making it a potential treatment for vitiligo.
• Apoptotic bodies: Their membrane-bound signals may contribute to resolving inflammatory events.

Conclusions

It is essential for both physicians and patients to be aware of and understand the main therapeutic alternatives available, evaluating their benefits and limitations. Non-cellular therapies represent promising options in regenerative medicine, with the potential to address various conditions safely and effectively.

The optimization of these treatments and their integration with other medical strategies will remain a key area of study in the coming years.

References

• Álvarez-Viejo M. (2020). Mesenchymal stem cells from different sources and their derived exosomes: A pre-clinical perspective. World J. Stem Cells. 12 (2): 100-109.
• Bar J., Lis-Nawara A. y Grelewski P.G. (2021). Dental Pulp stem cell-derived secretome and its regenerative potential. J. Mol. Sct. 22. 12018.
• Li X., Zhang D., Yu Y., Wang L. y Zhao M. (2023). Umbilical cord-derived mesenchymal stem cell secretome promotes skin regeneration and rejuvenation: From mechanism to therapeutics. Cell Prolif. 57.
• Martinez-Martinez A., Ruiz-Santiago F. y García-Espinosa J. (2018). Plasma rico en plaquetas: ¿mito o realidad?. Radiología. 60 (6): 465-475.
• Miyares C., Hollands M., Miyares E. y Pernas A. (2009). Efectividad de un extracto de placenta humana con calcio (Melagenina Plus) en el tratamiento del vitíligo. Revista Cubana de Investigaciones Biomédicas. 28 (3): 9-24.
• Sanchez-Losilla C., Ferré-Aniorte A., Álvarez-Díaz P., Barastegui-Fernández D., Cugat R. y Alentorn-Geli E. (2024). Eficacia del plasma rico en plaquetas en la reparación del manguito rotador: revisión sistemática y metaanálisis. Revista Española de cirugía ortopédica y traumatología. 68: 296-305.

Author: Biol. Fernando Vallejo Santin.