Stem cell-based therapies are defined as the administration of live cells to stimulate endogenous healing mechanisms, modulate immune response, and repair or replace damaged tissues. The most common sources of these include mesenchymal stem cells, hematopoietic stem cells, induced pluripotent stem cells, and neural stem cells.

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  Mesenchymal stem cells (MSCs): These cells, classified as multipotent stem cells, are most commonly derived from bone marrow (bone marrow aspiration for stem cells or bone marrow aspirate concentrate [BMACs]), adipose tissue (adipose-derived stem cells or ADSCs), and human umbilical cord. MSCs can differentiate into bone, cartilage, and tendon cells while also modulating inflammatory pathways. Although the exact mechanism is not fully understood, studies suggest that MSCs do not primarily work by directly differentiating into target tissues. Instead, their therapeutic effects are more likely mediated through paracrine signaling that promotes a coordinated healing response.

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  Hematopoietic stem cells (HSCs): HSCs are oligopotent stem cells and harvested from red bone marrow (primary site for HSCs), peripheral blood, and human umbilical cord. These are primarily utilized in hematologic disorders but theoretically have regenerative applications.

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  Induced pluripotent stem cells (iPSCs): First introduced in 2006, these are somatic cells reprogrammed into a pluripotent state, offering potential for personalized regenerative therapies. However, there is concern of consequential malignant transformation.

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  Neural stem cells (NSCs): NSCs are defined as multipotent cells with the ability to delineate into all parts of the central nervous system. They are currently known to exist in the subventricular and subgranular zones of the mammalian brain.

These are non–stem cell-related biologic products that look to stimulate or enhance the body’s natural healing processes. The most commonly used and studied include platelet-rich plasma (PRP), autologous conditioned serum (ACS), and amniotic and placental derivatives.

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  PRP: PRP treatment involves taking a concentration of autologous platelets and injecting them into targeted areas with the goal of releasing growth factors and stimulating healing. There is high variability in PRP preparations, dosing, and delivery methods. The most common current preparations include autologous conditioned plasma (ACP), leukocyte-rich PRP (LR-PRP), leukocyte-poor PRP (LP-PRP), platelet-rich fibrin (PRF), and platelet lysate (PL).

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    ACP: ACP, developed by Arthrex, is an LP-PRP. Studies have not demonstrated superiority over other PRP preparations.

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    LR-PRP and LP-PRP: As the name implies, these are PRP formulations with varying leukocyte concentrations relative to whole blood. Given that LR-PRP may increase the expression of catabolic proinflammatory molecules, there is some debate as to the utility of each type of PRP and their target tissue. Presently, the current evidence favors leukocyte-rich PRP.

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    PRF: This is another formulation of PRP where a fibrin matrix is introduced to offer a scaffold. Recent studies examining outcomes following arthroscopic tendon repair have found no significant benefit from adding MSCs compared to arthroscopic surgery alone.

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    PL: This is a derivative developed to combat the theoretic risk of vascular occlusion and platelet aggregation. There is evidence that PL injection provides similar benefit compared to other platelet-derived therapies.

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  ACS: This biologic therapy is developed by first collecting the patient’s blood, which is allowed to coagulate, followed by incubation of the serum. The resulting serum is rich with anti-inflammatory cytokines, particularly interleukin-1 receptor antagonist, interleukin (IL)-4, IL-10, and IL-13.

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  Amniotic and placental derivatives: As a group, these are biologic therapies harvested from amniotic fluid, amniotic membranes, umbilical cord blood, Wharton’s jelly, and human placenta. They contain growth factors, extracellular matrix proteins, and anti-inflammatory cytokines. Though currently used for wound healing barriers, their innate anti-inflammatory properties have been proposed for use as injectable solutions.

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  Peptide therapies: These are naturally occurring human peptides that are either synthetically made or harvested, concentrated, and then administered in a multitude of methods (primarily oral, intramuscular, or via subcutaneous injection). Current popular peptides include Body Protective Compound-157 (BPC-157), Thymosin Beta-4 Fragment (TB-4 or TB500 if synthetic), and glycyl- l -histidyl- l -lysine-copper. These are originally derived from gastric juice, thymus tissue, and plasma, saliva, or urine, respectively.

This therapy utilizes manipulation and modification of expression in human genes for therapeutic use. The current utility of this type of regenerative medicine centers around hematologic and cancer-related illnesses.

This method utilizes the natural role of these cellular delivery methods to carry proteins, lipids, RNA, and mRNA to influence the behavior of other cells with the goal of essentially mimicking stem cell therapy without the introduction of live cells. This degree of cellular control has been associated in the literature with the potential for restoration of cartilage and neural tissues. ^,

This method typically involves the creation of a scaffold, which is then seeded or implanted with biologic materials. Current examples that fit in this category are skin grafts, vascular grafts, and organ replacement.

There are a multitude of therapies that may be utilized to stimulate the body’s intrinsic repair systems without introduction of biologic material. These include, but are not limited to, electrical stimulation, magnetic stimulation, mechanical loading, ultrasound therapy, thermal therapy, percutaneous tenotomy, ozone therapy, proliferative therapy, or prolotherapy (most commonly hypertonic dextrose solution injection) and photobiomodulation.

A comprehensive understanding of governmental rules and regulations is fundamental to a physician’s responsibilities in the practice of regenerative medicine. To aid with this, the United States Food and Drug Administration (FDA) has attempted to clarify their stance on different therapies and how to safely use them. Most regenerative medicine falls under the category of human cells, tissues and cellular and tissue-based products (HCT/Ps). These are defined by the FDA in Title 21 of the Code of Federal Regulations, Part 1271 as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” Under Title 21 of the Code of Federal Regulations, Part 1271, the FDA has divided biologic therapies into a risk-based, 3 tiered system (exempt from HCT/Ps, Section 351 , and Section 361 ). Each of these categories have corresponding criteria and regulation as outlined later.

Section 351

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