What’s all the fuss about Regenerative Medicine?
In popular media, the term Regenerative Medicine, or Stem Cell Therapy, are becoming buzz words. This is because the field of medicine and healthcare is expanding and advancing every day, and many new treatments for otherwise common ailments are being discovered. These conditions range from burns, joint pain, strain, and pretty much every other common ailment out there.
Many patients have given up hope with trying to find traditional medicines that work. This is why many people are flocking to try Regenerative Medicine. This is also something that many people who are into holistic healing are trying, as it is simply the body working to heal itself.
Regenerative Medicine works as it takes a sample of your own blood, bone marrow, and other tissues, and then it goes through a process in which to take out a certain material known as Platelet-Rich Plasma. This PRP is then applied to the infected area, so that your body’s own platelets can work to heal your body back to full health, without having to worry about any invasive surgeries.
A good question to ask is why our body does this do this itself. Well, this is because research has shown that by isolating them, they activate, and as a result when injected back into the body start to work harder to fix the issues, such as in a joint, or helping to relieve pain. Many patients who try it say they have gotten good results from the treatment.
Many doctors predict that this therapy will help physicians provide a more non-intrusive treatment that has fewer side effects, and can be big within the coming years. Many compare it to the invention of penicillin with how important it is. It is even growing in popularity with many physicians using training courses to help their patients, leaving many of them happier and healthier.
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Platelet-Rich Plasma Injections: Protocol Guide
Almost all sports medicine doctors would agree that there’s no harm in trying Platelet Rich Plasma Injections (PRP Injections) for their patients. After all, there are hundreds of thousands of cases of positive results. All it needs is research to prove it’s worth. Currently there are many independent researches going on from private funding like the one conducted by Dr. Kimberly G. Harmon M.D., director of the Primary Care Sports Medicine fellowship at University of Washington. She just recently received a gift to support her research from UW alumni who I’m guessing firmly believes in Platelet-Rich Plasma (PRP).
While the process of extracting PRP is fairly simple — there are many variants as long as platelets are above baseline levels with at least seven growth factors — many physician are still unsure about what they can and can’t do when it comes to this marvelous procedure. So today I want to take the time to shine light on the fine print.
Platelet-Rich Plasma Injections Protocol
PRP: Protocols, Technique and Safety Endorsements
Usually, the procedure requires the physician/surgeon and an assistant or two to help with the preparation of graft, the maintenance of sterile technique and saving the ultrasound images (if relevant).
There should always be a specific indication associated with a physical exam with confirmed imaging studies such as an ultrasound, Cat Scan, or an MRI before treatment.
Proper patient education and a discussion must be had with the patient as well as a signed informed consent prior to the procedure.
Contraindications reviewed prior to procedure.
The patient is to positioned in a comfortable seated or reclining position.
Sterile single needles and syringes must be used with proper handling and disposal.
Using an aseptic procedure, the proper amount of blood is then drawn from the vein for the PRP procedure.
If the blood cannot be obtained from the site the first, time a new site must be used to prevent early activation.
Using a sterile technique, transfer the tube of venous blood to the centrifuge. Platelet Rich Plasma should be acquired using a separating device created for autologous blood. Preference is always given to a closed system that will prevent exposure of the blood and its cellular modules to the open air, and permits minimal use of the tissue.
Image Guidance PRP Therapy
Real time imaging guidance using ultrasound CT, or fluoroscopy should always be used when performing a PRP injection.
If ultrasound is going to be used, the subsequent considerations need to be decided on in advance: For lengthy procedures, PRP injections near the spine and intra-articular injections sterile gel is recommended.
Always use sterile probe covers. Cleansing the probe before and after the PRP procedures and observance to sterile technique is sufficient.
Guided images and ineradicable markings of the site of the probe position and the needle entry always needs to be made before cleaning the skin where the probe and needle will be inserted.
Always apply a bandage or a dressing after the procedure to protect the entry site from germs.
The patient should be monitored for any post PRP procedure complications such as vaso-vagal.
The patients should be given their post procedure directions and precautions and any questions should be answered before they leave, they should also have emergency contact information.
Patients should also be instructed about the immobilization and any post procedure activity that is allowed and/or not allowed.
Post PRP procedure pain prescriptions need to be given to the patient before discharge and any questions they may have about the medication(s) should be answered at this time. The patient also needs to be instructed to avoid NSAIDs till they have healed, are pain free, has full function has returned to the area being treated (or at least to the limited area being treated.
Per OSHA guidelines contaminated areas must be disinfected, before the next patient uses the room (area.)
The PRP procedure must be documented in detail, which includes a procedure note that contains the following information: date, pre and post procedure diagnosis, name of the procedure, physician/surgeon(s), any assistants, whether or not anesthesia was used, and if so what type, short-term indication of the procedure, a description of the graft preparation, a description of the procedure that includes any/all guidance and instruments used.
Platelet-Rich Plasma Injections Protocol
Patients are normally re-examined in 2-6 weeks after the PRP procedure to follow-up on pain, use, the injection site and to discuss any concerns and any future course of action.
The patient response of the treatment should be recorded using authenticated outcome measures.
Any complications responses and all other relevant information should be logged into in the ICMS tracking system.
The consideration for another PRP injection should be the center of the discussion and the patient will be able to make a decision based on the outcome.
With every medical procedure universal precautions must be used including before, during and after the procedure.
Risk of infection – PRP is antimicrobial and provides effective protection against most bacterial infections except for Klebsiella, Pseudomonas, and Enterococcus.
With the graft being made entirely out of autologous it basically eliminates the apprehension for the transmission of disease unless the graft became contaminated.
Risks to Patient from the Procedure
Lack of result
Loss of limb and death are very rare but possible.
Platelet Rich Plasma: Indications
Musculoskeletal complaints, require a complete history and exam to find a diagnosis. Often times, diagnostic studies may be needed and reviewed to understand why prior treatments failed. PRP is usually considered an optional treatment for chronic and subacute conditions. Commonly, healing slows down or stops all together at the 6-12 weeks’ period following an acute or traumatic injury. If the patient has not had any improvement for over the first six weeks, it’s probable the healing period has stopped.
Platelet-Rich Plasma Injections Protocol
Platelet Rich Plasma: Contraindications
Platelet dysfunction syndrome
Localized infection at the procedure site
Patient not willing to take the risks involved with the procedure
Regular use of NSAIDs within 48 hours of the PRP procedure
HGB of < 10 g/dl
Platelet count of < 105/ul
Systemic use of corticosteroids within 2 weeks
Recent illness or fever
Cancer – particularly hematopoietic or of the bone
HGB < 10 g/dl • Platelet count < 105/ul
Corticosteroid injection at treatment site within 1 month
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What’s True About Platelet-Rich Plasma For Stretch Marks?
Cindy is a career woman. So when she became pregnant for the first time, she was confused about which aspect of her life had higher priority – her work or taking care of her growing body. Not wanting to drown in that confusion, she kept herself busy with her work all day while snacking every little free time she had. This meant she was putting on a lot of weight, fast. Occasionally, her more experienced sister would remind her to apply Bio Oil on her growing tummy before bed, but she was too exhausted to actually do it. Except maybe for a few nights.
It wasn’t until after she delivered her baby that she realized her folly – her belly now looked like a road map.
What Works For Stretch Marks?
Sure, there are a variety of topical treatments, the ones with cocoa butter are the trend, but they’ll hardly affect severe stretch marks. They perform better when used as preventive measures. Because fully developed stretch marks are rarely skin deep. The stretching occurs on the layer underneath the surface called dermis. And the inability of the surface layer (epidermis) to keep up with the stretching is what’s causing the appearance of deep roads of stretch marks.
One way to “cure” stretch marks or at least the appearance of stretch marks is to make the skin surrounding the stretch marks a level closer to the stretch mark itself. This can be done by various minimally invasive “scarring” technologies like microdermabrasion, microneedling and CO2 fractional laser.
But You Said Platelet-Rich Plasma For Stretch Marks, Didn’t You?
Yes. But you see, platelets can only supply growth factors wherever healing is initiated. So unless healing is initiated or is still ongoing (not in the case of a fully developed stretch mark), the injected Platelet-Rich Plasma may not be able to produce it’s excellent results.
That’s why in forums you can hear a lot of advice from doctors who claim Platelet-Rich Plasma can’t help stretch marks. In fact, that’d be the first thing I’d say if someone asked me.
However, what if we could artificially initiate the healing? Not only in the outer epidermis layer, but also in the underlying dermis layer too? Now, that’s an excellent opportunity to put the growth factors in Platelet-Rich Plasma to good use, wouldn’t you agree?
Platelet-Rich Plasma For Stretch Marks
Actually that’s exactly how hundreds of thousands of happy men and women get rid of their stretch marks, around the world.
Enter PRP Microneedling
PRP microneedling is nothing but swapping Vitamin C that’s used in traditional microneedling with Platelet-Rich Plasma. This is traditionally called Platelet-Rich Plasma facial – due to the fact that you’re essentially spreading blood components over your face. This is a particularly effective treatment for the face. But it can provide even better results for stretch marks (probably the most effective treatment for stretch marks.)
Here’s why this particular combination really works:
- Getting to the root of the situation
With micro-needling, what we’re actually doing is punching some holes on both the outer epidermis layer and the inner dermis layer of the skin. These holes are so micro that it restores back to normal within minutes or hours. However, during the time it’s open a healing response is triggered. The very act of triggering a healing response in the inner dermis layer means there’s going to be some improvement on the stretch marks – as that’s where the source is. That’s probably why doctors recommend micro-needling for stretch marks over any other treatments. The procedure also removes unwanted, half-dead cells from the outer skin causing the stretch marks to appear less deep.
- Accelerated Healing With PRP
PRP’s job is to accelerate the healing response triggered by the micro needles, and it must do so during the time it’s open. So immediately after the micro-needling, a concentrated gel of PRP is applied. And massaged well enough for the platelets to actually seep through the holes. These platelets first stop the micro-bleeding caused by the microneedles and then the growth factors in the platelets trigger the production of a substantial amount of collagen. Now, collagen’s primary role is replacement of dead skin cells. Which means, it’ll replace all the dead, broken and torn skin cells in the entire area. The result is fresh new skin in the areas of the stretch mark causing it to actually shrink in size and look more rejuvenated.
Why Platelet-Rich Plasma?
Platelet-Rich Plasma is a powerful healing component. That’s why it was invented in the first place. In 1987, surgeons found that autologous platelet-rich plasma and red blood cell concentrates diminishes the cost of healing for cardiac surgery — meaning faster, efficient and natural healing for patients. Now, the same force that heals a cardiac surgery also can also cause rejuvenation of our body — whether it’s the skin or any other organ in the body. We’re only beginning to peel layers of healing potential found in Platelet-Rich Plasma. A 2015 chinese study about growth factors in PRP says it can even heal bones. They’re not the only ones. Here’s another study of PRP for bone grafts and they found it helps too.
So it’d be outright foolish to not use such a potent, natural healing agent for skin rejuvenation purposes. And micro-needling seems to be just what Platelet-Rich Plasma needs to exercise its healing powers. It’s much better than stockpiling tons of topical products that might “cure” stretch marks — scar creams, retinoids, and peptides.
Platelet-Rich Plasma For Stretch Marks
The More Earlier The Better
In healing, studies show platelets have much better efficiency when they are introduced right after the wound initiation. The same is the case for stretch marks. As soon as you see those marks, it’s better to head straight to the clinic and get a Platelet-Rich Plasma + Micro-needling session to heal it. The longer you wait, the more harder it gets to wipe them off. So stop experimenting with topical creams – they’re meant to be used as preventive measures.
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Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise
Although the clinical demand for bioengineered blood vessels continues to rise, current options for vascular conduits remain limited. The synergistic combination of emerging advances in tissue fabrication and stem cell engineering promises new strategies for engineering autologous blood vessels that recapitulate not only the mechanical properties of native vessels but also their biological function. Here we explore recent bioengineering advances in creating functional blood macro and microvessels, particularly featuring stem cells as a seed source. We also highlight progress in integrating engineered vascular tissues with the host after implantation as well as the exciting pre-clinical and clinical applications of this technology.
Ischemic diseases, such as atherosclerotic cardiovascular disease (CVD), remain one of the leading causes of mortality and morbidity across the world (GBD 2015 Mortality and Causes of Death Collaborators, 2016, Mozaffarian et al., 2016). These diseases have resulted in an ever-persistent demand for vascular conduits to reconstruct or bypass vascular occlusions and aneurysms. Synthetic grafts for replacing occluded arterial vessels were first introduced in the 1950s following surgical complications associated with harvesting vessels, the frequent shortage of allogeneic grafts, and immunologic rejection of large animal-derived vessels. However, despite advances in pharmacology, materials science, and device fabrication, these synthetic vascular grafts have not significantly decreased the overall mortality and morbidity (Nugent and Edelman, 2003, Prabhakaran et al., 2017). Synthetic grafts continue to exhibit a number of shortcomings that have limited their impact. These shortcomings include low patency rates for small diameter vessels (< 6 mm in diameter), a lack of growth potential for the pediatric population necessitating repeated interventions, and the susceptibility to infection. In addition to grafting, vascular conduits are also needed for clinical situations such as hemodialysis, which involves large volumes of blood that must be withdrawn and circulated back into a patient several times a week for several hours.
In addition to large-scale vessel complications, ischemic diseases also arise at the microvasculature level (< 1 mm in diameter), where replacing upstream arteries would not address the reperfusion needs of downstream tissues (Hausenloy and Yellon, 2013, Krug et al., 1966). Microvascularization has proven to be a critical step during regeneration and wound healing, where the delay of wound perfusion (in diabetic patients, for example) significantly slows down the formation of the granulation tissue and can lead to severe infection and ulceration (Baltzis et al., 2014, Brem and Tomic-Canic, 2007, Randeria et al., 2015).
In order to design advanced grafts, it is important to take structural components of a blood vessel into consideration, as understanding these elements is required for rational biomaterial design and choosing an appropriate cell source. Many of the different blood vessel beds also share some common structural features. Arteries, veins, and capillaries have a tunica intima comprised of endothelial cells (EC), which regulate coagulation, confer selective permeability, and participate in immune cell trafficking (Herbert and Stainier, 2011, Potente et al., 2011). Arteries and veins are further bound by a second layer, the tunica media, which is composed of smooth muscle cells (SMC), collagen, elastin, and proteoglycans, conferring strength to the vessel and acting as effectors of vascular tone. Arterioles and venules, which are smaller caliber equivalents of arteries and veins, are comprised of only a few layers of SMCs, while capillaries, which are the smallest vessels in size, have pericytes abutting the single layer of ECs and basement membrane. Vascular tissue engineering has evolved to generate constructs that incorporate the functionality of these structural layers, withstand physiologic stresses inherent to the cardiovascular system, and promote integration in host tissue without mounting immunologic rejection (Chang and Niklason, 2017).
A suitable cell source is also critical to help impart structural stability and facilitate in vivo integration. Patient-derived autologous cells are one potential cell source that has garnered interest because of their potential to minimize graft rejection. However, isolating and expanding viable primary cells to a therapeutically relevant scale may be limited given that patients with advanced arterial disease likely have cells with reduced growth or regenerative potential. With the advancement of stem cell (SC) technology and gene editing tools such as CRISPR, autologous adult and induced pluripotent stem cells (iPSCs) are emerging as promising alternative sources of ECs and perivascular SMCs that can be incorporated into the engineered vasculature (Chan et al., 2017, Wang et al., 2017).
Importantly, a viable cell source alone is not sufficient for therapeutic efficacy. Although vascular cells can contribute paracrine factors and have regenerative capacity, merely delivering a dispersed mixture of ECs to the host tissue has shown limited success at forming vasculature or integrating with the host vasculature (Chen et al., 2010). Therefore, recent tissue engineering efforts have instead focused on recreating the architecture and the function of the vasculature in vitro before implantation, with the hypothesis that pre-vascularized grafts and tissues enhance integration with the host. In this review, we explore recent advances in fabricating blood vessels of various calibers, from individual arterial vessels to vascular beds comprised of microvessels, and how these efforts facilitate the integration of the implanted vasculature within a host. We also discuss the extent to which SC-derived ECs and SMCs have been incorporated into these engineered tissues.
The first reported successful clinical application of TEBV in patients was performed by Shin’oka et al., who implanted a biodegradable construct as a pulmonary conduit in a child with pulmonary atresia and single ventricle anatomy (Shin’oka et al., 2001). The construct was composed of a synthetic polymer mixture of L-lactide and e-caprolactone, and it was reinforced with PGA and seeded with autologous bone marrow-derived mesenchymal stem cells (BM-MSCs). The authors demonstrated patency and patient survival 7 months post-implant, and expanded their study to a series of 23 implanted TEBVs and 19 tissue patch repairs in pediatric patients (Hibino et al., 2010). They were noted to have no graft-related mortality, and four patients required interventions to relieve stenosis at a mean follow-up of 5.8 years. The first sheet-based technology to seed cultured autologous cells, developed by L’Heureux et al., was iterated by the group to induce cultured fibroblast cell sheet over a 10-week maturation period and produce tubules of endogenous ECM over a production time ranging between 6 and 9 months. They dehydrated and provided a living adventitial layer before seeding the constructs with ECs (L’Heureux et al., 2006). Their TEBV, named the Lifeline graft, was implanted in 9 of 10 enrolled patients with end-stage renal disease on hemodialysis and failing access grafts in a clinical trial. Six of the nine surviving patients had patent grafts at 6 months, while the remaining grafts failed due to thrombosis, rejection, and failure (McAllister et al., 2009). An attempt to create an “off the shelf” version of this graft in which pre-fabricated, frozen scaffolds were seeded with autologous endothelium prior to implantation led to 2 of the 3 implanted grafts failing due to stenosis, and one patient passed away due to graft infection (Benrashid et al., 2016).
Most recently, results were reported for the phase II trial of the decellularized engineered vessel Humacyte in end-stage renal disease patients surgically unsuitable for arterio-venous fistula creation (Lawson et al., 2016). This clinical scenario offers a relatively captive patient population in which graft complications are unlikely to be limb or life-threatening, and infectious and thrombotic event rates for traditional materials such as ePTFE are high (Haskal et al., 2010). The manufacturers seeded a 6mm PGA scaffold with SMCs from deceased organ and tissue donors and decellularized the scaffold following ECM production in an incubator coupled with a pulsatile pump prior to implantation. Humacyte demonstrated 63% primary patency at 6 months, 28% at 12 months, and 18% at 18 months post-implant in 60 patients. Ten grafts were abandoned. However, 12-month patency and mean procedure rate of 1.89 per patient-year to restore patency were comparable to PTFE grafts, while higher secondary patency rates were observed (89% versus 55%–65% at 1 year) (Huber et al., 2003, Lok et al., 2013). Although Humacyte revealed no immune sensitization and a lower infection rate than PTFEs (reported up to 12%) (Akoh and Patel, 2010), there remains much work to be done to improve primary patency and reduce the need for interventions.
Harnessing the regenerative functions reported in ECs derived from adult stem cells and iPSCs offers the promise of improving TEBV patency. Mcllhenny et al. generated ECs from adipose-derived stromal cells, transfected them with adenoviral vector carrying the endothelial nitric oxide synthase (eNOS) gene, and seeded the ECs onto decellularized human saphenous vein scaffolds (McIlhenny et al., 2015). They hypothesized that through inhibition of platelet aggregation and adhesion molecule expression, nitric oxide synthesis would prevent thrombotic occlusion in TEBV. Indeed, they reported patency with a non-thrombogenic surface 2 months post-implantation in rabbit aortas. While introducing additional complexities, engineering ECs and SMCs with other regenerative, anti-inflammatory, anti-thrombotic genes could perhaps bridge the functional difference between SC-derived cells and native primary cells.
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