Peek behind the paper: disease-dependent drug delivery in allograft protection

In this feature, Praveen Vemula (inStem; Bangalore, India) peeks behind his review paper evaluating the current and future states of allograft preservation by employing novel, disease-dependent drug release technology.

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Nov 20, 2019

Please could you introduce yourself and your institute?

I am an associate investigator at the Institute for Stem Cell Biology and Regenerative Science (inStem; Bangalore, India). My research interests center around developing novel biomaterials, bioengineering concepts and chemical entities to solve unmet clinical needs. I run an academic lab that focuses on translational clinical research with two main focuses: i) biomaterials and ii) chemical biology. In our biomaterials program we develop innovative materials and drug delivery concepts to mitigate the limitations associated with existing drugs and enhance their therapeutic efficacy. As part of our chemical biology program, we run a drug discovery program and work to develop new chemical entities as potential drug candidates for the treatment of inflammatory diseases. Additionally, my lab focuses on building a successful entrepreneurship program to translate the technologies we develop in the lab into the clinic/market.

Why is allograft preservation important in regenerative and other reconstructive areas of medicine?

Our body’s defense systems are designed to recognize ‘self’ entities and identify foreign entities as threats. The immune system, the very unit designed to protect one from infections and deadly pathogens, turns into a foe for patients who receive allografts. Unlike solid/internal organ transplants – where finding matched donors is possible – finding matched donors for allografts in the field of reconstructive surgery is often not feasible.

Often when designing biomaterials, the focus is on what the implantable biomaterials can do to the body...equally important is what the body can do to biomaterials; this is often neglected.”

Therefore, aggressive rejection episodes have been observed in allograft transplantations. Various medications and methods to curb the immune system from rejecting allografts have been developed and, so far, such host immunosuppression has been fairly effective at preventing rejection episodes. In unfortunate cases of allograft rejection, finding another allograft donor is a daunting task and can result in amputation. Given these limitations, it is of paramount importance to protect allografts post-transplantation.      

What prompted you to conduct this review?

I started developing drug delivery systems for protecting allografts against recipient immune rejection as a postdoctoral fellow in Jeffrey Karp’s lab at the Brigham and Women’s Hospital (MA, USA). One of the major hurdles in protecting transplanted allografts is the required local administration of immunosuppressant drugs. To overcome this, my lab developed a novel, on-demand method for disease-responsive – or inflammation-responsive – drug release to protect allografts via localized immunosuppression. Following great success of this approach, we wanted to share our concept with the wider field and review state-of-the-art approaches researchers have been developing to protect transplanted allografts.

How may nano- and biomaterials allow for localized, stimuli-responsive and long-term delivery of drugs, and what implications/benefits may these have for reconstructive surgeries?

The efficacy of numerous nano- and biomaterials at protecting grafts in reconstructive surgery have been evaluated with limited success; this likely results from a mismatch of drug release and disease condition. Immune activation – and its associated inflammation – fluctuates highly in grafts. However, current biomaterials provide sustained drug release over days, weeks or months – irrespective of the disease level. Drugs may be released when they are not needed and then, when the disease-state flares up, there can be no drug depot left to release. Thus far, there is no reliable, non-invasive diagnostic test available to measure the level of immune activation/inflammation a patient has. Hence, developing an innovative approach where disease-severity acts as the stimulus for drug release has represented an urgent, unmet clinical need.

In 2014, we demonstrated that locally-injectable, immunosuppressant-laden hydrogels – that can release drugs in response to inflammation – have excellent potential to protect vascularized composite tissue allografts in rodent models. Since then, we have demonstrated the efficacy of inflammation-responsive hydrogels at protecting allografts in a swine model as well. We anticipate that such systems will be fine-tuned to effectively protect allografts in humans as well; this will have a significant impact on the quality of lives of graft recipients, such as soldiers or accident victims.

What are some of the limitations to biomaterial-based drug delivery approaches and how may we look to overcome these?

Often when designing biomaterials, the focus is on what the implantable biomaterials can do to the body. Biomaterial parameters such as having an optimum drug release profile, biodegradability and biocompatibility receive a great deal of attention. However, equally important is what the body can do to biomaterials; this is often neglected. In the context of biomaterials protecting transplanted allografts, the lifetime of the implanted biomaterial plays a key role. Each biomaterial has an optimum drug loading capacity in a given volume. Therefore, it is critical to see how long an implanted biomaterial can stay at the site of injection.

Close inspection must be made to get an idea of depot drug depletion and to determine the next dose of administration. This is often misjudged because the concentration of systemic drug in the serum is quantified and used as an approximation of whether there is any drug left in the depot. However, this can be inaccurate as the depot releases the drug such that it has a higher, local tissue concentration but a lower, undetectable systemic concentration. Therefore, strategies should be developed to get accurate information about the lifetime of the drug depot.

…there is an unmet need to design an implantable, biomaterial-based device in the transplanted allograft that can measure and enable the onset of an early rejection episode.”

One way to overcome this is to co-encapsulate an imaging agent with the drug, which can give us a handle to follow the presence of biomaterial using non-invasive imaging methods. However, the challenge in this approach would be establishing a direct correlation between the release of the drug and imaging agent; whether the release of the imaging agents can be used as a surrogate method to follow drug release must be established.

What is the importance of biocompatibility and correct biomaterial choice to reconstructive surgery success/ implant rejection?

The survival of a graft depends entirely on the right choice of biomaterial; it is crucial to choose the right material for the correct application to improve the success of transplant surgery. It is of prime importance to consider the required drug release profile before choosing the biomaterial. Many long-term biomaterial strategies fail because patients’ immune systems target the biomaterials and, as a result, the material’s drug release profile changes. Choosing a biomaterial that is more native, or can be broken down into non-harmful compounds without stimulating the immune response, is one of the holy grails in the field of biomaterials.

The system we have described in our work biodegrades completely into non-harmful products and is responsive to inflammation because of the presence of ester groups. Thus, the system serves the dual purpose of better biocompatibility and correct chemistry to make it a viable option for immunotherapeutics, in vivo.

What is the importance of developing novel rejection diagnostic methods to surgery success?

One of the major hurdles in preventing rejection is the absence of reliable, non-invasive rejection diagnostic methods. Often, rejection episodes begin in deep tissues; by the time visual signs appear, it may be too late to effectively treat. The current, most reliable method for determining rejection is tissue biopsy. However, collecting frequent biopsies of the graft is not a practically feasible approach and can lead to non-compliance. 

The use of biomaterial-based strategies in reconstructive surgeries is still in its infancy.”

Therefore, there is an unmet need to design an implantable, biomaterial-based device in the transplanted allograft that can measure and enable the onset of an early rejection episode. A great deal of interdisciplinary work is required to develop a reliable, implantable detection device; developing such a system would have a huge impact in the field of reconstructive surgery.  

How do you see the future use of biomaterials in reconstructive surgeries evolving?

The use of biomaterial-based strategies in reconstructive surgeries is still in its infancy. There is huge scope for innovation in this field to develop advanced/smart biomaterials with improved drug loading and disease-responsiveness. Approaches may be designed to use biomaterials for early detection of a rejection episode. Additionally, implanted biomaterials from which depletion of drugs can be followed reliably will enable the more accurate delivery of drugs. There is also a need to develop new strategies for improving the drug loading capacity of biomaterials without compromising their efficacy. Sustained drug delivery for prolonged periods is another challenge yet to be overcome. There is also a major need to develop efficient topical and transdermal systems for vascularized composite allotransplantations, as the skin is one of the most immunogenic sites.


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