Stem Cells Therapy: 6 Current Clinical Applications
Stem cells are undifferentiated cells with the ability to self-renew and develop into various cell types. They are essential in regenerative medicine, aiming to repair and replace damaged tissues and organs through transplantation.
Plastic surgery and regenerative medicine share similarities in using a patient's own tissue to enhance the body. There are different types of stem cells, including embryonic stem cells (ESCs), which have significant potential but face ethical and safety concerns. Adult stem cells, like mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), are more practical options for clinical applications due to their ease of isolation and differentiation capabilities. Adipose-derived stem cells (ADSCs) are particularly promising as they can be easily harvested and have a high yield and differentiation potential.
However, the clinical applications of stem cell therapies are still limited, and challenges such as engraftment, safety, and efficacy need to be addressed. Further research is required to fully utilize stem cell regenerative techniques in plastic surgery.
In this blog, we discuss possible areas where stem cell therapy can be applied, including soft tissue regeneration, bone, cartilage, peripheral nerves, wound healing, and addressing skin aging.
1. Soft Tissue Regeneration
The regeneration and enhancement of soft tissue involve maintaining aesthetic results over the long term. Current therapies, such as biomaterials, have limitations due to potential complications and high cost. Other options include composite tissue flaps and autologous fat transplantation (fat grafting). Fat grafting is commonly used for various indications like facial lipodystrophy, lower limb atrophy, and breast augmentation and reconstruction. The autologous fat used in fat grafting contains adipose-derived stem cells (ADSCs), which support tissue regeneration by secreting angiogenic growth factors. However, fat grafts have varying rates of resorption and can lead to unreliable long-term outcomes.
A technique called cell-assisted lipotransfer (CAL) combines aspirated fat with concentrated ADSCs to create ADSC-rich fat grafts, improving the survival rate and reducing adverse effects of the procedure. Preliminary studies suggest that ADSCs might enhance the retention and volume-restoring capabilities of transplanted fat. Further well-controlled clinical trials comparing CAL with traditional fat grafting are needed to draw definitive conclusions.
Researchers have also explored alternative ADSC therapies for soft tissue regeneration. For instance, immature adipocytes differentiated from ADSCs have shown promise in treating depressed scars with significant volume recovery. Another approach, stem cell-enriched tissue (SET) injections, involves injecting isolated autologous ADSCs into areas that previously received fat grafts. This model reduces operating room time and procedure costs compared to CAL, but larger randomized trials are necessary to determine its efficacy.
A noteworthy development is the FDA's regulation of autologous adipose stem cells from stromal vascular fraction (SVF) as "drugs" due to the use of collagenase during component separation. Surgeons planning to use SVF must now go through a costly and time-consuming investigational new drug (IND) application process with an approved Institutional Review Board (IRB). Research into other methods of separating cells and stroma, such as mechanical separation by centrifugation and rapid isolation techniques, may be necessary to address the implications of these new regulations.
2. Bone Reconstruction
Autologous bone grafts have been the standard for reconstructing bony defects, but complications and donor site morbidity have led researchers to explore cell-based therapies. Both bone marrow-derived stem cells (BMSCs) and adipose-derived stem cells (ADSCs) have shown promise for bone regeneration in laboratory studies.
Clinical stem cell therapies for bone regeneration have shown encouraging results for craniofacial defects, particularly calvarial defects that cannot naturally ossify in patients over two years old. ADSCs combined with autologous cancellous bone and fibrin glue have successfully repaired large calvarial defects, leading to new bone formation. Similarly, ADSCs seeded in β-tricalcium phosphate (TCP) granules have effectively repaired critical-size calvarial defects without using autologous bone grafting.
Stem cell treatments have also been used for maxilla and mandible defects, involving a multistep procedure with ADSC or BMSC transplants combined with growth factors in a scaffold. The implanted cells, after some time, are transplanted with surrounding tissue to fill the bony defect. Alternatively, a one-stage procedure called in situ bone formation utilizes ADSCs seeded on a scaffold to fill a mandibular defect without the need for ectopic bone formation. These approaches have shown promising clinical and histologic outcomes.
While these cell-based treatments have shown potential, more research is needed to fully understand the mechanisms behind bone formation and to compare the efficacy of different cell-based approaches.
3. Cartilage Formation
Cartilage defects pose a challenge as cartilage has limited natural self-repair capacity. The only FDA-approved cellular-based therapy for such defects is autologous chondrocyte implantation (ACI), where chondrocytes are harvested, expanded in culture, and then injected back into the defect. ACI shows promising early clinical results, but it has limitations, including difficulty maintaining chondrocyte characteristics and donor site morbidity. Researchers have explored alternative cellular therapies, focusing on progenitor cell populations like bone marrow-derived stem cells (BMSCs). Clinically, autologous BMSCs have been used to repair articular cartilage defects through surgical transplantation or intra-articular injections, leading to improved clinical symptoms.
Adipose-derived stem cells (ADSCs) have also been investigated as a less invasive source of chondrocyte progenitors that can be differentiated into cartilage cells in vitro. Using appropriate growth factors and a 3-dimensional environment, ADSCs can form cartilage tissue in vivo. Additionally, uninduced ADSCs have been transplanted into cartilage defects in animals, resulting in complete restoration of native cartilage structure and full defect repair. By limiting ex vivo manipulation, ADSCs show promise for future clinical applications and demonstrate their ability to adapt to the environment in vivo without requiring external growth factors or substrates before transplantation.
4. Wound Healing
The wound healing process involves complex interactions among cells, growth factors, and extracellular matrix molecules, aiming to achieve hemostasis, cell proliferation, angiogenesis, re-epithelialization, and tissue remodeling. Adipose-derived stem cells (ADSCs) have been considered promising candidates for wound therapies due to their secretion of essential growth factors and cytokines crucial for wound healing. Studies, like the one by Rigotti et al., demonstrate the reparative capabilities of ADSCs in treating severe radiation-induced lesions, leading to clinical improvements and neovessel formation. Similar positive outcomes have been observed in animal models of radiation injury, where ADSCs increased vessel density in wounds.
ADSCs have shown potential benefits in wounds complicated by ischemia, such as critical limb ischemia. Intramuscular injections of ADSCs have improved pain scores and walking distances in patients with thromboangiitis obliterans and diabetic feet. ADSC transplantation into ischemic limbs has increased blood flow and collateral vessel formation. Autologous transplantation of other cell types, like BMSCs, has also shown promising results in limb ischemia patients, although some adverse effects have been noted with bone marrow mononuclear cells.
ADSCs may also be suitable for treating pathological wound healing associated with aberrant scar formation. Scar formation is closely linked to the inflammatory process in wound healing. ADSCs' anti-inflammatory and immunosuppressive effects have shown promise in reducing scar formation in animal models. However, controlling inflammatory modulation will be crucial to strike a balance between necessary and excessive scar formation, as scar formation is an essential part of normal wound healing.
5 .Skin Rejuvenation
Skin aging is characterized by various degenerative processes, notably a reduction in collagen production by fibroblasts. To rejuvenate the skin, certain cytokines and growth factors stimulate fibroblast collagen synthesis. Interestingly, these factors are also present in the secretome of ADSCs, indicating that these cells could potentially aid in repairing atrophic and photo-damaged skin. Animal studies have shown that subcutaneous injections of ADSCs increase dermal thickness and collagen density in aged mice while reducing UVB-induced wrinkles. These effects are thought to result from the paracrine activation of dermal fibroblasts and dermal angiogenesis. In a clinical pilot study, intradermal injection of autologous lipoaspirate (PLA) cells containing around 20% to 30% ADSCs led to improved skin texture and fewer wrinkles in one patient after two months, with an increase in dermal thickness observed through ultrasonography. Though these outcomes are promising, further research is needed to fully understand the mechanisms underlying ADSC therapies before wider application in skin rejuvenation.
6. Peripheral Nerve Regeneration
The repair of peripheral nerve injuries (PNIs), especially those with significant defects, is hindered by issues like donor site complications and suboptimal functional recovery. As a result, there has been a growing interest in exploring alternative treatments involving various regenerative therapies. Most experimental stem cell treatments for PNI aim to replace host support cells, particularly the essential Schwann-cell population. Schwann cells play a vital role in supporting axon regeneration by providing trophic, structural, and directional support.
Neural stem cells are a promising option as they are natural precursors to Schwann cells and have shown improved regeneration in animal models of PNI. However, their use is constrained by challenges in isolation and ethical concerns. Similarly, embryonic stem cells (ESCs) have been employed to promote nerve repair in animals, but they also face similar limitations.
On the other hand, adult stem cells, such as bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived stem cells (ADSCs), offer advantages as they can be obtained from the patient's own body (autologous cells) and possess multipotent properties. BMSCs can be trans-differentiated into Schwann cell-like cells, and ADSCs have demonstrated the ability to replace host Schwann cells and promote nerve regeneration when differentiated into neuronal-like lineages. ADSCs are more easily accessible than BMSCs and have comparable regenerative capabilities for peripheral nerves.
Stem cells sourced from the skin, particularly from the hair follicle bulge, also show promise. These undifferentiated adult stem cells can be differentiated into neuron-like and Schwann cell-like cells. Additionally, neural crest precursor cells found in the dermis have been shown to improve nerve regeneration in chronically denervated nerves.
Beyond cell replacement, alternative approaches to peripheral nerve regeneration involve modulating the nerve injury site to provide trophic support for host cells. Studies have shown that undifferentiated ADSCs transplanted into peripheral nerve injuries secrete various neurotrophic factors, which support axon regeneration. ADSCs also express genes associated with glial phenotypes, suggesting their potential to create a conducive environment for regenerating axons. However, the precise mechanism behind ADSCs' influence on nerve regeneration requires further investigation, either as a paracrine influence that promotes regeneration in the surrounding tissue or as a progenitor cell that replaces host tissues.
To advance translational studies in this field, it is essential to gain a better understanding of ADSCs' role and their impact on nerve regeneration, be it through paracrine effects or direct cell replacement.
Conclusion
Regenerative medicine has made significant strides in understanding stem cell biology and its applications in clinical treatments. Plastic surgery has also benefited from stem cell therapies, showing positive outcomes in treating various defects, non-healing wounds, and aesthetic procedures like breast augmentation and skin rejuvenation. The use of ADSCs has been particularly successful due to their easy isolation and efficient culture for clinical applications. However, the specific mechanisms behind these therapeutic effects remain unclear, warranting further research into transplanted cell survival, controlled proliferation, and integration into the surrounding environment.
While case reports and small series have provided a foundation for future experiments, larger randomized trials will be essential to establish the safety and efficacy of these novel treatments. The recent advances in stem cell therapies offer promise for the future of regenerative medical therapies in plastic surgery. Nonetheless, careful and controlled implementation of cell-based therapies will be crucial to ensure the appropriate translation of this technology into clinical practice.
Reference:
Stem Cells and Plastic Surgery (2019)
The use of stem cells in plastic and reconstructive surgery (2014)
Stem cell and research in plastic surgery (2014)
Stem Cells in Plastic Surgery: A Review of Current Clinical and Translational Applications (2013)
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